177 results on '"Burbulla, Lena F."'
Search Results
2. Dopamine metabolism by a monoamine oxidase mitochondrial shuttle activates the electron transport chain
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Graves, Steven M, Xie, Zhong, Stout, Kristen A, Zampese, Enrico, Burbulla, Lena F, Shih, Jean C, Kondapalli, Jyothisri, Patriarchi, Tommaso, Tian, Lin, Brichta, Lars, Greengard, Paul, Krainc, Dimitri, Schumacker, Paul T, and Surmeier, D James
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Biological Psychology ,Biomedical and Clinical Sciences ,Neurosciences ,Psychology ,Animals ,Dopamine ,Dopaminergic Neurons ,Electron Transport ,Energy Metabolism ,Humans ,Male ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Mitochondria ,Monoamine Oxidase ,Oxidation-Reduction ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
Monoamine oxidase (MAO) metabolizes cytosolic dopamine (DA), thereby limiting auto-oxidation, but is also thought to generate cytosolic hydrogen peroxide (H2O2). We show that MAO metabolism of DA does not increase cytosolic H2O2 but leads to mitochondrial electron transport chain (ETC) activity. This is dependent upon MAO anchoring to the outer mitochondrial membrane and shuttling electrons through the intermembrane space to support the bioenergetic demands of phasic DA release.
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- 2020
3. Identification of ASCL1 as a determinant for human iPSC-derived dopaminergic neurons
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Earley, Aaron M., Burbulla, Lena F., Krainc, Dimitri, and Awatramani, Rajeshwar
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- 2021
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4. Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers
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Sugier, Pierre-Emmanuel, Lucotte, Elise A., Domenighetti, Cloé, Law, Matthew H., Iles, Mark M., Brown, Kevin, Amos, Christopher, McKay, James D., Hung, Rayjean J., Karimi, Mojgan, Bacq-Daian, Delphine, Boland-Augé, Anne, Olaso, Robert, Deleuze, Jean-François, Lesueur, Fabienne, Ostroumova, Evgenia, Kesminiene, Ausrele, de Vathaire, Florent, Guénel, Pascal, consortium, The Epithyr, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimios, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Nakayama, Akiyoshi, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Guedes, Leonor Correia, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy, Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Rödström, Emil Ygland, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Landoulsi, Zied, consortium, Courage-PD, Truong, Thérèse, Elbaz, Ales, JPND Courage-PD [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], and Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center]
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Male ,Lung Neoplasms ,Parkinson's disease ,Neurology [D14] [Human health sciences] ,RESEARCH ARTICLES ,RESEARCH ARTICLE ,SDG 3 - Good Health and Well-being ,genetics [Parkinson Disease] ,Risk Factors ,pleiotropy ,Humans ,cancer ,ddc:610 ,genetics [Genetic Predisposition to Disease] ,Ovarian Neoplasms ,Neurologie [D14] [Sciences de la santé humaine] ,Prostatic Neoplasms ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,genetic correlation ,parkinson's disease ,polygenic risk score ,epidemiology [Melanoma] ,Neurology ,genetics [Melanoma] ,genetics [Polymorphism, Single Nucleotide] ,Female ,epidemiology [Parkinson Disease] ,Genetics & genetic processes [F10] [Life sciences] ,Neurology (clinical) ,Génétique & processus génétiques [F10] [Sciences du vivant] ,Genome-Wide Association Study - Abstract
BackgroundEpidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties.ObjectiveWe used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors.MethodsWe used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses.ResultsWe confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31).ConclusionsWe show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
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- 2023
5. Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease
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Burbulla, Lena F., Song, Pingping, Mazzulli, Joseph R., Zampese, Enrico, Wong, Yvette C., Jeon, Sohee, Santos, David P., Blanz, Judith, Obermaier, Carolin D., Strojny, Chelsee, Savas, Jeffrey N., Kiskinis, Evangelos, Zhuang, Xiaoxi, Krüger, Rejko, Surmeier, D. James, and Krainc, Dimitri
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- 2017
6. Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers
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Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], JPND Courage-PD [sponsor], Sugier, Pierre-Emmanuel, Lucotte, Elise A., Domenighetti, Cloé, Law, Matthew H., Iles, Mark M., Brown, Kevin, Amos, Christopher, McKay, James D., Hung, Rayjean J., Karimi, Mojgan, Bacq-Daian, Delphine, Boland-Augé, Anne, Olaso, Robert, Deleuze, Jean-François, Lesueur, Fabienne, Ostroumova, Evgenia, Kesminiene, Ausrele, de Vathaire, Florent, Guénel, Pascal, consortium, The Epithyr, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimios, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Nakayama, Akiyoshi, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Guedes, Leonor Correia, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy, Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Rödström, Emil Ygland, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Landoulsi, Zied, consortium, Courage-PD, Truong, Thérèse, Elbaz, Ales, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], JPND Courage-PD [sponsor], Sugier, Pierre-Emmanuel, Lucotte, Elise A., Domenighetti, Cloé, Law, Matthew H., Iles, Mark M., Brown, Kevin, Amos, Christopher, McKay, James D., Hung, Rayjean J., Karimi, Mojgan, Bacq-Daian, Delphine, Boland-Augé, Anne, Olaso, Robert, Deleuze, Jean-François, Lesueur, Fabienne, Ostroumova, Evgenia, Kesminiene, Ausrele, de Vathaire, Florent, Guénel, Pascal, consortium, The Epithyr, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimios, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Nakayama, Akiyoshi, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Guedes, Leonor Correia, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy, Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Rödström, Emil Ygland, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Landoulsi, Zied, consortium, Courage-PD, Truong, Thérèse, and Elbaz, Ales
- Abstract
Background Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. Objective We used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. Methods We used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses. Results We confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly dri
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- 2023
7. Interactions of dopamine, iron, and alpha-synuclein linked to dopaminergic neuron vulnerability in Parkinson's disease and Neurodegeneration with Brain Iron Accumulation disorders
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Wise, Rachel M., primary, Wagener, Annika, additional, Fietzek, Urban M., additional, Klopstock, Thomas, additional, Mosharov, Eugene V., additional, Zucca, Fabio A., additional, Sulzer, David, additional, Zecca, Luigi, additional, and Burbulla, Lena F., additional
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- 2022
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8. Loss of Mortalin Function in Parkinson’s Disease-Supporting the Mitochondrial Pathway of Neurodegeneration
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Burbulla, Lena F., Krüger, Rejko, Kaul, Sunil C., editor, and Wadhwa, Renu, editor
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- 2012
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9. Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence From the COURAGE-PD Consortium
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Grover, Sandeep, Kumar Sreelatha, Ashwin Ashok, Landoulsi, Zied, May, Patrick, Bobbili, Dheeraj, Edsall, Connor, Bartusch, Felix, Hanussek, Maximilian, Krüger, Jens, Hernandez, Dena G, Blauwendraat, Cornelis, Mellick, George D, Pihlstrom, Lasse, Zimprich, Alexander, Pirker, Walter, Tan, Manuela, Rogaeva, Ekaterina, Lang, Anthony, Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Domenighetti, Cloé, Chartier-Harlin, Marie-Christine, Mutez, Eugenie, Brockmann, Kathrin, Deutschländer, Angela B, Hadjigeorgiou, Georges M, Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Schulte, Claudia, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Burbulla, Lena F, Matsuo, Hirotaka, Sugier, Pierre-Emmanuel, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Pavelka, Lukas, van de Warrenburg, Bart P C, Bloem, Bastiaan R, Singleton, Andrew B, Aasly, Jan, Radivojkov-Blagojevic, Milena, Toft, Mathias, Guedes, Leonor Correia, Ferreira, Joaquim J, Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Lichtner, Peter, Pedersen, Nancy L, Ran, Caroline, Belin, Andrea C, Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E, Morrison, Karen E, Krainc, Dimitri, Farrer, Matt J, Kruger, Rejko, Mohamed, Océane, Elbaz, Alexis, Gasser, Thomas, Sharma, Manu, Genetics, and the Comprehensive Unbiased Risk Factor Assessment for, Disease, Environment in Parkinson's, Portugal, Berta, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), FOR2488, INTER/DFG/17/11583046, INTER/DFG/19/14429377, Michael J. Fox Foundation for Parkinson's Research, MJFF, EU Joint Programme – Neurodegenerative Disease Research, JPND: 01ED1406, Multiple System Atrophy Coalition, MSA, European Commission, EC: EP1802749, Deutsche Forschungsgemeinschaft, DFG: DFG/SH 599/6-1, Fonds National de la Recherche Luxembourg, FNR: FNR/P13/6682797, Bundesministerium für Bildung und Forschung, BMBF, Université Paris-Saclay, The COURAGE-PD Consortium is conducted under a partnership agreement between 35 studies. The COURAGE-PD Consortium is supported by the EU Joint Program for Neurodegenerative Disease Research (JPND, neurodegenerationresearch.eu/initiatives/annual-calls-for-proposals/closed-calls/risk-factors-2012/risk-factor-call-results/courage-pd/ , Grant ID: 01ED1406)., and The Article Processing Charge was funded by the authors.
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parkinson’s disease ,[SDV]Life Sciences [q-bio] ,burden of disease ,Polymorphism, Single Nucleotide ,Duration of disease ,genetic heritability ,duration of disease ,genetics [Parkinson Disease] ,age at onset ,Humans ,Genetic Predisposition to Disease ,ddc:610 ,Age of Onset ,genetics [Genetic Predisposition to Disease] ,Burden of disease ,Age at onset ,Parkinson Disease ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Courage ,Parkinson’s disease ,Genetic heritability ,Female ,Neurology (clinical) ,epidemiology [Parkinson Disease] ,Genome-Wide Association Study - Abstract
Background and ObjectivesConsiderable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations.MethodsA meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium. This was followed by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson Disease Genomics Consortium (IPDGC).ResultsThe COURAGE-PD Consortium included a cohort of 8,535 patients with PD (91.9%: Europeans and 9.1%: East Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD = 11.6), with an underrepresentation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE = 0.057). None of the loci reached genome-wide significance (p < 5 × 10−8). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance (p < 0.025): (rs34311866: β(SE)COURAGE = 0.477(0.203), pCOURAGE = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (Ntotal = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361: β(SE)COURAGE+IPDGC = 0.720(0.122), pCOURAGE+IPDGC = 3.13 × 10−9) and a novel BST1 locus (rs4698412: β(SE)COURAGE+IPDGC = −0.526(0.096), pCOURAGE+IPDGC = 4.41 × 10−8).DiscussionOur study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.
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- 2022
10. Genome-wide Association and Meta-analysis of Age-at-Onset in Parkinson Disease: Evidence From COURAGE-PD Consortium 10.1212/WNL.0000000000200699
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Grover, Sandeep, Ashwin, Ashok Kumar Sreelatha, Pihlstrom, Lasse, Domenighetti, Cloé, Schulte, Claudia, Sugier, Pierre-Emmanuel, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Mohamed, Océane, Portugal, Berta, Landoulsi, Zied, May, Patrick, Bobbili, Dheeraj Reddy, Edsall, Connor, Bartusch, Felix, Hanussek, Maximilian, Krüger, Jens, Hernandez, Dena G., Blauwendraat, Cornelis, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Tan, Manuela, Rogaeva, Ekaterina, Lang, Anthony, Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugenie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Burbulla, Lena F., Matsuo, Hirotaka, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Pavelka, Lukas, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Singleton, Andrew B., Aasly, Jan, Toft, Mathias, Guedes, Leonor Correia, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy L., Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E., Morrison, Karen E., Krainc, Dimitri, Farrer, Matt J., Krüger, Rejko, Elbaz, Alexis, Gasser, Thomas, Sharma, Manu, of, On Behalf, Genetics, The Comprehensive Unbiased Risk Factor Assessment For, consortium, Environment In Parkinson Textquoterights Disease Courage-P. D., Fonds National de la Recherche - FnR [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], and Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center]
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Neurologie [D14] [Sciences de la santé humaine] ,Parkinson's disease ,Neurology [D14] [Human health sciences] ,Age of onset ,GWAS ,Genetics & genetic processes [F10] [Life sciences] ,Génétique & processus génétiques [F10] [Sciences du vivant] - Abstract
Background and Objectives: Considerable heterogeneity exists in the literature concerning genetic determinants of the age of onset (AAO) of Parkinson\textquoterights disease (PD), which could be attributed to lack of well-powered replication cohorts. The previous largest GWAS identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on AAO of PD, these have not been independently replicated. The present study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations.Methods: A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson\textquoterights Disease (COURAGE-PD) consortium. This was followed up by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson disease Genomics Consortium (IPDGC).Results: The COURAGE-PD included a cohort of 8,535 patients with PD (91.9\%: Europeans, 9.1\%: East-Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD=11.6), with an under-representation of females (40.2\%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE=0.057). None of the loci reached genome-wide significance (P\
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- 2022
11. The Interaction between HLA-DRB1 and Smoking in Parkinson's Disease Revisited
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Domenighetti, Cloé, Douillard, Venceslas, Sugier, Pierre-Emmanuel, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Gourraud, Pierre-Antoine, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Nakayama, Akiyoshi, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Correia Guedes, Leonor, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy L., Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Ygland Rödström, Emil, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, KraincMD, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Vince, Nicolas, Elbaz, Alexis, Genetics, Comprehensive Unbiased Risk Factor Assessment For, Consortium, Environment In Parkinson S Disease Courage-P. D., Fonds National de la Recherche - FnR [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], and Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center]
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Neurologie [D14] [Sciences de la santé humaine] ,genetics [HLA-DRB1 Chains] ,Neurology [D14] [Human health sciences] ,Parkinson's disease ,Smoking ,Parkinson Disease ,genetics [Smoking] ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Polymorphism, Single Nucleotide ,smoking ,gene-environment interaction ,HLA ,Neurology ,genetics [Parkinson Disease] ,genetics [Polymorphism, Single Nucleotide] ,Humans ,Genetic Predisposition to Disease ,ddc:610 ,Genetics & genetic processes [F10] [Life sciences] ,Neurology (clinical) ,Génétique & processus génétiques [F10] [Sciences du vivant] ,HLA-DRB1 Chains - Abstract
Contains fulltext : 282469.pdf (Publisher’s version ) (Open Access) BACKGROUND: Two studies that examined the interaction between HLA-DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions. OBJECTIVE: To perform a large-scale independent replication of the HLA-DRB1 × smoking interaction. METHODS: We genotyped 182 single nucleotide polymorphism (SNPs) associated with smoking initiation in 12 424 cases and 9480 controls to perform a Mendelian randomization (MR) analysis in strata defined by HLA-DRB1. RESULTS: At the amino acid level, a valine at position 11 (V11) in HLA-DRB1 displayed the strongest association with PD. MR showed an inverse association between genetically predicted smoking initiation and PD only in absence of V11 (odds ratio, 0.74, 95% confidence interval, 0.59-0.93, P(Interaction) = 0.028). In silico predictions of the influence of V11 and smoking-induced modifications of α-synuclein on binding affinity showed findings consistent with this interaction pattern. CONCLUSIONS: Despite being one of the most robust findings in PD research, the mechanisms underlying the inverse association between smoking and PD remain unknown. Our findings may help better understand this association. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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- 2022
12. Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study
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Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Fonds National de la Recherche - FnR [sponsor], JPND Courage-PD [sponsor], Domenighetti, Cloé, Sugier, Pierre-Emmanuel, Ashok Kumar Sreelatha, Ashwin, Schulte, Claudia, Grover, Sandeep, Mohamed, Océane, Portugal, Berta, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Correia Guedes, Leonor, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy L., Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Elbaz, Alexis, Genetics, The Comprehensive Unbiased Risk Factor Assessment For, Consortium, Environment In Parkinson S Disease Courage-P. D., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Fonds National de la Recherche - FnR [sponsor], JPND Courage-PD [sponsor], Domenighetti, Cloé, Sugier, Pierre-Emmanuel, Ashok Kumar Sreelatha, Ashwin, Schulte, Claudia, Grover, Sandeep, Mohamed, Océane, Portugal, Berta, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Correia Guedes, Leonor, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy L., Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Elbaz, Alexis, Genetics, The Comprehensive Unbiased Risk Factor Assessment For, and Consortium, Environment In Parkinson S Disease Courage-P. D.
- Abstract
Background Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. Objective The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR). Methods We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). Results Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95 confidence interval = 1.12–2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37–4.56], P = 0.003; P-difference with women = 0.029). Conclusions Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society
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- 2022
13. Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study
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Domenighetti, Cloé, Sugier, Pierre-Emmanuel, Lichtner, Peter, Singleton, Andrew B, Hernandez, Dena Michelle Godwin, Edsall, Connor, Mellick, George D, Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E, Koks, Sulev, Ashok Kumar Sreelatha, Ashwin, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B, Hadjigeorgiou, Georges M, Dardiotis, Efthimos, Schulte, Claudia, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Grover, Sandeep, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, Mohamed, Océane, van de Warrenburg, Bart P C, Bloem, Bastiaan R, Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Correia Guedes, Leonor, Ferreira, Joaquim J, Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Portugal, Berta, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy L, Ran, Caroline, Belin, Andrea C, Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E, May, Patrick, Morrison, Karen E, Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F, Farrer, Matt J, Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Elbaz, Alexis, Genetics, and the Comprehensive Unbiased Risk Factor Assessment for, Bobbili, Dheeraj R, Disease, Environment in Parkinson's, Radivojkov-Blagojevic, Milena, and Repositório da Universidade de Lisboa
- Subjects
Male ,dairy intake ,Parkinson's disease ,Mendelian randomization ,Parkinson Disease ,Dairy intake ,Mendelian Randomization Analysis ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Polymorphism, Single Nucleotide ,Neurology ,genetics [Parkinson Disease] ,Risk Factors ,adverse effects [Dairy Products] ,genetics [Polymorphism, Single Nucleotide] ,Humans ,Genetic Predisposition to Disease ,Female ,Dairy Products ,Neurology (clinical) ,ddc:610 ,epidemiology [Parkinson Disease] ,genetics [Genetic Predisposition to Disease] ,Genome-Wide Association Study - Abstract
© 2022 International Parkinson and Movement Disorder Society, Background: Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. Objective: The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR). Methods: We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). Results: Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12-2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37-4.56], P = 0.003; P-difference with women = 0.029). Conclusions: Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society., This study used data from the Courage-PD consortium, conducted under a partnership agreement among 35 studies. The Courage-PD consortium is supported by the EU Joint Program for Neurodegenerative Disease research (JPND; https://www.neurodegenerationresearch.eu/initiatives/annual-calls-for-proposals/closed-calls/risk-factors-2012/risk-factor-call-results/courage-pd/). C.D. is the recipient of a doctoral grant from Université Paris-Saclay, France. P.M. was funded by the Fonds National de Recherche (FNR), Luxembourg, as part of the National Centre of Excellence in Research on Parkinson's Disease (NCER-PD, FNR11264123) and the DFG Research Units FOR2715 (INTER/DFG/17/11583046) and FOR2488 (INTER/DFG/19/14429377). A.B.S., D.G.H., and C.E. are funded by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services, project ZO1 AG000949. E.R. is funded by the Canadian Consortium on Neurodegeneration in Aging. S.K. is funded by MSWA. P.T. is the recipient of an Estonian Research Council Grant PRG957. E.M.V. is funded by the Italian Ministry of Health (Ricerca Corrente 2021). S.B. and J.C. are supported by grants from the National Research Foundation of South Africa (grant number: 106052); the South African Medical Research Council (Self-Initiated Research Grant); and Stellenbosch University, South Africa; they also acknowledge the support of the NRF-DST Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; and Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town. P.P. and M.D.-F. have received funding from the Spanish Ministry of Science and Innovation (SAF2013-47939-R). K.W. and N.L.P. are funded by the Swedish Research Council, grant numbers K2002-27X-14056-02B, 521-2010-2479, 521-2013-2488, and 2017-02175. N.L.P. is funded by the National Institutes of Health, grant numbers ES10758 and AG 08724. C.R. is funded by the Märta Lundkvist Foundation, Swedish Brain Foundation, and Karolinska Institutet Research Fund. A.C.B. is funded by the Swedish Brain Foundation, Swedish Research Council, and Karolinska Institutet Research Funds. M.T. (M. Tan) is funded by the Parkinson's UK. M.S. was supported by grants from the German Research Council (DFG/SH 599/6-1), MSA Coalition, and The Michael J. Fox Foundation (USA Genetic Diversity in PD Program: GAP-India Grant ID: 17473). PG GEN sample collection was funded by the MRC and UK Medical Research Council (C.E.C. and K.E.M.).
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- 2022
14. Converging environmental and genetic pathways in the pathogenesis of Parkinson's disease
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Burbulla, Lena F. and Krüger, Rejko
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- 2011
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15. Mitochondrial Phenotypes in Parkinson’s Diseases—A Focus on Human iPSC-Derived Dopaminergic Neurons
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Heger, Leonie M., primary, Wise, Rachel M., additional, Hees, J. Tabitha, additional, Harbauer, Angelika B., additional, and Burbulla, Lena F., additional
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- 2021
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16. Direct targeting of wild-type glucocerebrosidase by antipsychotic quetiapine improves pathogenic phenotypes in Parkinson’s disease models
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Burbulla, Lena F., primary, Zheng, Jianbin, additional, Song, Pingping, additional, Jiang, Weilan, additional, Johnson, Michaela E., additional, Brundin, Patrik, additional, and Krainc, Dimitri, additional
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- 2021
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17. Mendelian randomization study of smoking, alcohol, and coffee drinking in relation to Parkinso's disease
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Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], JPND [sponsor], Domenighetti, Cloe, Sugier, Pierre Emmanuel, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, Mohamed, Oceane, Portugal, Berta, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaieva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Hardin, Marie-Christophe, Mutez, Eugenie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza-Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotak, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart Pc, Bloom, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrom, Lasse, Guedes, Leonor Correia, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Farien, Monica, Wirdefeldt, Karin, Pedersen, Nancy L., Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, DImitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Elbaz, Alexis, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], JPND [sponsor], Domenighetti, Cloe, Sugier, Pierre Emmanuel, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, Mohamed, Oceane, Portugal, Berta, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaieva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Hardin, Marie-Christophe, Mutez, Eugenie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza-Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotak, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart Pc, Bloom, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrom, Lasse, Guedes, Leonor Correia, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Farien, Monica, Wirdefeldt, Karin, Pedersen, Nancy L., Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, DImitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, and Elbaz, Alexis
- Abstract
Background:Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson’s disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective:To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods:We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). Results:We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60–0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion:Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.
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- 2021
18. A novel heterozygous OPA3 mutation located in the mitochondrial target sequence results in altered steady-state levels and fragmented mitochondrial network
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Grau, Tanja, Burbulla, Lena F, Engl, Gertraud, Delettre, Cécile, Delprat, Benjamin, Oexle, Konrad, Leo-Kottler, Beate, Roscioli, Tony, Krüger, Rejko, Rapaport, Doron, Wissinger, Bernd, and Schimpf-Linzenbold, Simone
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- 2013
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19. A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's disease.
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Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Developmental and Cellular Biology (Schwamborn Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group) [research center], Luxembourg Centre for Contemporary and Digital History (C2DH) > Digital Research Infrastructure (DRI) [research center], Fonds National de la Recherche - FnR [sponsor], German Research Council [sponsor], EU Joint Program-Neurodegenerative Diseases [sponsor], European Union Horizon2020 research and innovation programme [sponsor], National Institutes of Health (NIH) [sponsor], Boussaad, Ibrahim, Obermaier, Carolin D., Hanss, Zoé, Bobbili, Dheeraj R., Bolognin, Silvia, Glaab, Enrico, Wołyńska, Katarzyna, Weisschuh, Nicole, De Conti, Laura, May, Caroline, Giesert, Florian, Grossmann, Dajana, Lambert, Annika, Kirchen, Susanne, Biryukov, Maria, Burbulla, Lena F., Massart, Francois, Bohler, Jill, Cruciani, Gérald, Schmid, Benjamin, Kurz-Drexler, Annerose, May, Patrick, Duga, Stefano, Klein, Christine, Schwamborn, Jens Christian, Marcus, Katrin, Woitalla, Dirk, Vogt Weisenhorn, Daniela M., Wurst, Wolfgang, Baralle, Marco, Krainc, Dimitri, Gasser, Thomas, Wissinger, Bernd, Krüger, Rejko, Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Developmental and Cellular Biology (Schwamborn Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group) [research center], Luxembourg Centre for Contemporary and Digital History (C2DH) > Digital Research Infrastructure (DRI) [research center], Fonds National de la Recherche - FnR [sponsor], German Research Council [sponsor], EU Joint Program-Neurodegenerative Diseases [sponsor], European Union Horizon2020 research and innovation programme [sponsor], National Institutes of Health (NIH) [sponsor], Boussaad, Ibrahim, Obermaier, Carolin D., Hanss, Zoé, Bobbili, Dheeraj R., Bolognin, Silvia, Glaab, Enrico, Wołyńska, Katarzyna, Weisschuh, Nicole, De Conti, Laura, May, Caroline, Giesert, Florian, Grossmann, Dajana, Lambert, Annika, Kirchen, Susanne, Biryukov, Maria, Burbulla, Lena F., Massart, Francois, Bohler, Jill, Cruciani, Gérald, Schmid, Benjamin, Kurz-Drexler, Annerose, May, Patrick, Duga, Stefano, Klein, Christine, Schwamborn, Jens Christian, Marcus, Katrin, Woitalla, Dirk, Vogt Weisenhorn, Daniela M., Wurst, Wolfgang, Baralle, Marco, Krainc, Dimitri, Gasser, Thomas, Wissinger, Bernd, and Krüger, Rejko
- Abstract
Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic forms of the disease. Using a patient-based in vitro model of PARK7-linked PD, we identified a U1-dependent splicing defect causing a drastic reduction in DJ-1 protein and, consequently, mitochondrial dysfunction. Targeting defective exon skipping with genetically engineered U1-snRNA recovered DJ-1 protein expression in neuronal precursor cells and differentiated neurons. After prioritization of candidate drugs, we identified and validated a combinatorial treatment with the small-molecule compounds rectifier of aberrant splicing (RECTAS) and phenylbutyric acid, which restored DJ-1 protein and mitochondrial dysfunction in patient-derived fibroblasts as well as dopaminergic neuronal cell loss in mutant midbrain organoids. Our analysis of a large number of exomes revealed that U1 splice-site mutations were enriched in sporadic PD patients. Therefore, our study suggests an alternative strategy to restore cellular abnormalities in in vitro models of PD and provides a proof of concept for neuroprotection based on precision medicine strategies in PD.
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- 2020
20. Modeling Brain Pathology of Niemann‐Pick Disease Type C Using Patient‐Derived Neurons
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Burbulla, Lena F., primary, Mc Donald, Jessica M., additional, Valdez, Clarissa, additional, Gao, Fanding, additional, Bigio, Eileen H., additional, and Krainc, Dimitri, additional
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- 2021
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21. The Convergence of Alpha-Synuclein, Mitochondrial, and Lysosomal Pathways in Vulnerability of Midbrain Dopaminergic Neurons in Parkinson’s Disease
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Minakaki, Georgia, primary, Krainc, Dimitri, additional, and Burbulla, Lena F., additional
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- 2020
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22. A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson’s disease
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Boussaad, Ibrahim, primary, Obermaier, Carolin D., additional, Hanss, Zoé, additional, Bobbili, Dheeraj R., additional, Bolognin, Silvia, additional, Glaab, Enrico, additional, Wołyńska, Katarzyna, additional, Weisschuh, Nicole, additional, De Conti, Laura, additional, May, Caroline, additional, Giesert, Florian, additional, Grossmann, Dajana, additional, Lambert, Annika, additional, Kirchen, Susanne, additional, Biryukov, Maria, additional, Burbulla, Lena F., additional, Massart, Francois, additional, Bohler, Jill, additional, Cruciani, Gérald, additional, Schmid, Benjamin, additional, Kurz-Drexler, Annerose, additional, May, Patrick, additional, Duga, Stefano, additional, Klein, Christine, additional, Schwamborn, Jens C., additional, Marcus, Katrin, additional, Woitalla, Dirk, additional, Vogt Weisenhorn, Daniela M., additional, Wurst, Wolfgang, additional, Baralle, Marco, additional, Krainc, Dimitri, additional, Gasser, Thomas, additional, Wissinger, Bernd, additional, and Krüger, Rejko, additional
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- 2020
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23. Gelator Length Precisely Tunes Supramolecular Hydrogel Stiffness and Neuronal Phenotype in 3D Culture
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Godbe, Jacqueline M., primary, Freeman, Ronit, additional, Burbulla, Lena F., additional, Lewis, Jacob, additional, Krainc, Dimitri, additional, and Stupp, Samuel I., additional
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- 2020
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24. Dissecting the role of the mitochondrial chaperone mortalin in Parkinsonʼs disease: functional impact of disease-related variants on mitochondrial homeostasis
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Burbulla, Lena F., Schelling, Carina, Kato, Hiroki, Rapaport, Doron, Woitalla, Dirk, Schiesling, Carola, Schulte, Claudia, Sharma, Manu, Illig, Thomas, Bauer, Peter, Jung, Stephan, Nordheim, Alfred, Schöls, Ludger, Riess, Olaf, and Krüger, Rejko
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- 2010
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25. Balance is the challenge – The impact of mitochondrial dynamics in Parkinsonʼs disease
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Burbulla, Lena F., Krebiehl, Guido, and Krüger, Rejko
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- 2010
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26. Variants in Miro1 Cause Alterations of ER-Mitochondria Contact Sites in Fibroblasts from Parkinson’s Disease Patients
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Berenguer-Escuder, Clara, primary, Grossmann, Dajana, additional, Massart, Franҫois, additional, Antony, Paul, additional, Burbulla, Lena F., additional, Glaab, Enrico, additional, Imhoff, Sophie, additional, Trinh, Joanne, additional, Seibler, Philip, additional, Grünewald, Anne, additional, and Krüger, Rejko, additional
- Published
- 2019
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27. Dopamine metabolism by a monoamine oxidase mitochondrial shuttle activates the electron transport chain
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Graves, Steven M., primary, Xie, Zhong, additional, Stout, Kristen A., additional, Zampese, Enrico, additional, Burbulla, Lena F., additional, Shih, Jean C., additional, Kondapalli, Jyothisri, additional, Patriarchi, Tommaso, additional, Tian, Lin, additional, Brichta, Lars, additional, Greengard, Paul, additional, Krainc, Dimitri, additional, Schumacker, Paul T., additional, and Surmeier, D. James, additional
- Published
- 2019
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28. The role of dopamine in the pathogenesis of GBA1-linked Parkinson's disease
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Burbulla, Lena F., primary and Krainc, Dimitri, additional
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- 2019
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29. A modulator of wild-type glucocerebrosidase improves pathogenic phenotypes in dopaminergic neuronal models of Parkinson’s disease
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Burbulla, Lena F., primary, Jeon, Sohee, additional, Zheng, Jianbin, additional, Song, Pingping, additional, Silverman, Richard B., additional, and Krainc, Dimitri, additional
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- 2019
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30. Correction to Conversion of Quinazoline Modulators from Inhibitors to Activators of β-Glucocerebrosidase
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Zheng, Jianbin, primary, Jeon, Sohee, additional, Jiang, Weilan, additional, Burbulla, Lena F., additional, Ysselstein, Daniel, additional, Oevel, Kristine, additional, Krainc, Dimitri, additional, and Silverman, Richard B., additional
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- 2019
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31. Conversion of Quinazoline Modulators from Inhibitors to Activators of β-Glucocerebrosidase
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Zheng, Jianbin, primary, Jeon, Sohee, additional, Jiang, Weilan, additional, Burbulla, Lena F., additional, Ysselstein, Daniel, additional, Oevel, Kristine, additional, Krainc, Dimitri, additional, and Silverman, Richard B., additional
- Published
- 2019
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32. Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson’s Disease
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Domenighetti, Cloé, Sugier, Pierre-Emmanuel, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, Mohamed, Océane, Portugal, Berta, May, Patrick, Bobbili, Dheeraj R., Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart PC, Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Guedes, Leonor Correia, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy L., Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, and Elbaz, Alexis
- Abstract
Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson’s disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). We found a significant inverse association between smoking initiation and PD (ORIVWper 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60–0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.
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- 2022
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33. Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells
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Seibler, Philip, primary, Burbulla, Lena F, primary, Dulovic, Marija, primary, Zittel, Simone, primary, Heine, Johanne, primary, Schmidt, Thomas, primary, Rudolph, Franziska, primary, Westenberger, Ana, primary, Rakovic, Aleksandar, primary, Münchau, Alexander, primary, Krainc, Dimitri, primary, and Klein, Christine, primary
- Published
- 2018
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34. Acid ceramidase inhibition ameliorates α-synuclein accumulation upon loss of GBA1 function
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Kim, Myung Jong, primary, Jeon, Sohee, additional, Burbulla, Lena F, additional, and Krainc, Dimitri, additional
- Published
- 2018
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- View/download PDF
35. Methamphetamine‐induced mitochondrial oxidant stress mediated by monoamine oxidase metabolism of dopamine
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Graves, Steven M, primary, Xie, Zhong, additional, Zampese, Enrico, additional, Stout, Kristen A, additional, Tai, Rex A, additional, Schwarzschild, Sarah E, additional, Burbulla, Lena F, additional, Krainc, Dimitri, additional, Schumacker, Paul T, additional, and Surmeier, D James, additional
- Published
- 2017
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36. Functional Impairment in Miro Degradation and Mitophagy Is a Shared Feature in Familial and Sporadic Parkinson’s Disease
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Hsieh, Chung-Han, primary, Shaltouki, Atossa, additional, Gonzalez, Ashley E., additional, Bettencourt da Cruz, Alexandre, additional, Burbulla, Lena F., additional, St. Lawrence, Erica, additional, Schüle, Birgitt, additional, Krainc, Dimitri, additional, Palmer, Theo D., additional, and Wang, Xinnan, additional
- Published
- 2016
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37. Human Neuron Cultures: Micropatterning Facilitates the Long-Term Growth and Analysis of iPSC-Derived Individual Human Neurons and Neuronal Networks (Adv. Healthcare Mater. 15/2016)
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Burbulla, Lena F., primary, Beaumont, Kristin G., additional, Mrksich, Milan, additional, and Krainc, Dimitri, additional
- Published
- 2016
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38. Micropatterning Facilitates the Long-Term Growth and Analysis of iPSC-Derived Individual Human Neurons and Neuronal Networks
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Burbulla, Lena F., primary, Beaumont, Kristin G., additional, Mrksich, Milan, additional, and Krainc, Dimitri, additional
- Published
- 2016
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39. Detection of Free and Protein-Bound ortho-Quinones by Near-Infrared Fluorescence
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Mazzulli, Joseph R., primary, Burbulla, Lena F., additional, Krainc, Dimitri, additional, and Ischiropoulos, Harry, additional
- Published
- 2016
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- View/download PDF
40. Acid ceramidase inhibition ameliorates α-synuclein accumulation upon loss of GBA1 function.
- Author
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Myung Jong Kim, Jeon, Sohee, Burbulla, Lena F., and Krainc, Dimitri
- Published
- 2018
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- View/download PDF
41. Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression.
- Author
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Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Reinhardt, Peter, Schmid, Benjamin, Burbulla, Lena F., Schondorf, David C., Wagner, Lydia, Glatza, Michael, Hoing, Susanne, Hargus, Gunnar, Heck, Susanna A., Dhingra, Ashutosh, Wu, Guangming, Muller, Stephan, Brockmann, Kathrin, Kluba, Torsten, Maisel, Martina, Krüger, Rejko, Berg, Daniela, Tsytsyura, Yaroslav, Thiel, Cora S., Psathaki, Olympia-Ekaterini, Klingauf, Jurgen, Kuhlmann, Tanja, Klewin, Marlene, Muller, Heiko, Gasser, Thomas, Scholer, Hans R., Sterneckert, Jared, Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Reinhardt, Peter, Schmid, Benjamin, Burbulla, Lena F., Schondorf, David C., Wagner, Lydia, Glatza, Michael, Hoing, Susanne, Hargus, Gunnar, Heck, Susanna A., Dhingra, Ashutosh, Wu, Guangming, Muller, Stephan, Brockmann, Kathrin, Kluba, Torsten, Maisel, Martina, Krüger, Rejko, Berg, Daniela, Tsytsyura, Yaroslav, Thiel, Cora S., Psathaki, Olympia-Ekaterini, Klingauf, Jurgen, Kuhlmann, Tanja, Klewin, Marlene, Muller, Heiko, Gasser, Thomas, Scholer, Hans R., and Sterneckert, Jared
- Abstract
The LRRK2 mutation G2019S is the most common genetic cause of Parkinson's disease (PD). To better understand the link between mutant LRRK2 and PD pathology, we derived induced pluripotent stem cells from PD patients harboring LRRK2 G2019S and then specifically corrected the mutant LRRK2 allele. We demonstrate that gene correction resulted in phenotypic rescue in differentiated neurons and uncovered expression changes associated with LRRK2 G2019S. We found that LRRK2 G2019S induced dysregulation of CPNE8, MAP7, UHRF2, ANXA1, and CADPS2. Knockdown experiments demonstrated that four of these genes contribute to dopaminergic neurodegeneration. LRRK2 G2019S induced increased extracellular-signal-regulated kinase 1/2 (ERK) phosphorylation. Transcriptional dysregulation of CADPS2, CPNE8, and UHRF2 was dependent on ERK activity. We show that multiple PD-associated phenotypes were ameliorated by inhibition of ERK. Therefore, our results provide mechanistic insight into the pathogenesis induced by mutant LRRK2 and pointers for the development of potential new therapeutics.
- Published
- 2013
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42. Knockdown of Hsc70-5/mortalin induces loss of synaptic mitochondria in a Drosophila Parkinson's disease model.
- Author
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Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Zhu, Jun-Yi, Vereshchagina, Natalia, Sreekumar, Vrinda, Burbulla, Lena F., Costa, Ana C., Daub, Katharina J., Woitalla, Dirk, Martins, Luisa, Krüger, Rejko, Rasse, Tobias M., Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Zhu, Jun-Yi, Vereshchagina, Natalia, Sreekumar, Vrinda, Burbulla, Lena F., Costa, Ana C., Daub, Katharina J., Woitalla, Dirk, Martins, Luisa, Krüger, Rejko, and Rasse, Tobias M.
- Abstract
Mortalin is an essential component of the molecular machinery that imports nuclear-encoded proteins into mitochondria, assists in their folding, and protects against damage upon accumulation of dysfunctional, unfolded proteins in aging mitochondria. Mortalin dysfunction associated with Parkinson's disease (PD) increases the vulnerability of cultured cells to proteolytic stress and leads to changes in mitochondrial function and morphology. To date, Drosophila melanogaster has been successfully used to investigate pathogenesis following the loss of several other PD-associated genes. We generated the first loss-of-Hsc70-5/mortalin-function Drosophila model. The reduction of Mortalin expression recapitulates some of the defects observed in the existing Drosophila PD-models, which include reduced ATP levels, abnormal wing posture, shortened life span, and reduced spontaneous locomotor and climbing ability. Dopaminergic neurons seem to be more sensitive to the loss of mortalin than other neuronal sub-types and non-neuronal tissues. The loss of synaptic mitochondria is an early pathological change that might cause later degenerative events. It precedes both behavioral abnormalities and structural changes at the neuromuscular junction (NMJ) of mortalin-knockdown larvae that exhibit increased mitochondrial fragmentation. Autophagy is concomitantly up-regulated, suggesting that mitochondria are degraded via mitophagy. Ex vivo data from human fibroblasts identifies increased mitophagy as an early pathological change that precedes apoptosis. Given the specificity of the observed defects, we are confident that the loss-of-mortalin model presented in this study will be useful for further dissection of the complex network of pathways that underlie the development of mitochondrial parkinsonism.
- Published
- 2013
43. A novel heterozygous OPA3 mutation located in the mitochondrial target sequence results in altered steady-state levels and fragmented mitochondrial network.
- Author
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Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Grau, Tanja, Burbulla, Lena F., Engl, Gertraud, Delettre, Cecile, Delprat, Benjamin, Oexle, Konrad, Leo-Kottler, Beate, Roscioli, Tony, Krüger, Rejko, Rapaport, Doron, Wissinger, Bernd, Schimpf-Linzenbold, Simone, Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Grau, Tanja, Burbulla, Lena F., Engl, Gertraud, Delettre, Cecile, Delprat, Benjamin, Oexle, Konrad, Leo-Kottler, Beate, Roscioli, Tony, Krüger, Rejko, Rapaport, Doron, Wissinger, Bernd, and Schimpf-Linzenbold, Simone
- Abstract
BACKGROUND: Mutations in OPA3 have been reported in patients with autosomal dominant optic atrophy plus cataract and Costeff syndrome. Here, we report the results of a comprehensive study on OPA3 mutations, including the mutation spectrum and its prevalence in a large cohort of OPA1-negative autosomal dominant optic atrophy (ADOA) patients, the associated clinical phenotype and the functional characterisation of a newly identified OPA3 mutant. METHODS: Mutation analysis was carried out in a patient cohort of 121 independent ADOA patients. To characterise a novel OPA3 mutation, we analysed the mitochondrial import, steady-state levels and the mitochondrial localisation of the mutated protein in patients' fibroblasts. Furthermore, the morphology of mitochondria harbouring the mutated OPA3 was monitored. RESULTS: We identified four independent cases (representing families with multiple affected members) with OPA3 mutations. Besides the known p.Q105E mutation, we observed a novel insertion, c.10_11insCGCCCG/p.V3_G4insAP which is located in the mitochondrial presequence. Detailed functional analysis of mitochondria harbouring this novel mutation demonstrates a fragmented mitochondrial network with a decreased mitochondrial mass in patient fibroblasts. In addition, quantification of the OPA3 protein reveals decreased steady-state levels of the mutant protein compared with the native one. Comparison of the clinical phenotypes suggests that OPA3 mutations can additionally evoke hearing loss and by that extend the clinical manifestation of OPA3-associated optic atrophy. This finding is supported by expression analysis of OPA3 in murine cochlear tissue. CONCLUSIONS: In summary, our study provides new insights into the clinical spectrum and the pathogenesis of dominant optic atrophy caused by mutations in the OPA3 gene.
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- 2013
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44. Knockdown of Hsc70-5/mortalin Induces Loss of Synaptic Mitochondria in a Drosophila Parkinson’s Disease Model
- Author
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Zhu, Jun-yi, primary, Vereshchagina, Natalia, additional, Sreekumar, Vrinda, additional, Burbulla, Lena F., additional, Costa, Ana C., additional, Daub, Katharina J., additional, Woitalla, Dirk, additional, Martins, L. Miguel, additional, Krüger, Rejko, additional, and Rasse, Tobias M., additional
- Published
- 2013
- Full Text
- View/download PDF
45. The use of primary human fibroblasts for monitoring mitochondrial phenotypes in the field of Parkinson's disease.
- Author
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Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Burbulla, Lena F., Krüger, Rejko, Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Burbulla, Lena F., and Krüger, Rejko
- Abstract
Parkinson's disease (PD) is the second most common movement disorder and affects 1% of people over the age of 60 (1). Because ageing is the most important risk factor, cases of PD will increase during the next decades (2). Next to pathological protein folding and impaired protein degradation pathways, alterations of mitochondrial function and morphology were pointed out as further hallmark of neurodegeneration in PD (3-11). After years of research in murine and human cancer cells as in vitro models to dissect molecular pathways of Parkinsonism, the use of human fibroblasts from patients and appropriate controls as ex vivo models has become a valuable research tool, if potential caveats are considered. Other than immortalized, rather artificial cell models, primary fibroblasts from patients carrying disease-associated mutations apparently reflect important pathological features of the human disease. Here we delineate the procedure of taking skin biopsies, culturing human fibroblasts and using detailed protocols for essential microscopic techniques to define mitochondrial phenotypes. These were used to investigate different features associated with PD that are relevant to mitochondrial function and dynamics. Ex vivo, mitochondria can be analyzed in terms of their function, morphology, colocalization with lysosomes (the organelles degrading dysfunctional mitochondria) and degradation via the lysosomal pathway. These phenotypes are highly relevant for the identification of early signs of PD and may precede clinical motor symptoms in human disease-gene carriers. Hence, the assays presented here can be utilized as valuable tools to identify pathological features of neurodegeneration and help to define new therapeutic strategies in PD.
- Published
- 2012
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- View/download PDF
46. Guidelines for the use and interpretation of assays for monitoring autophagy.
- Author
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Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Klionsky, Daniel J., Abdalla, Fabio C., Abeliovich, Hagai, Abraham, Robert T., Acevedo-Arozena, Abraham, Adeli, Khosrow, Agholme, Lotta, Agnello, Maria, Agostinis, Patrizia, Aguirre-Ghiso, Julio A., Ahn, Hyung Jun, Ait-Mohamed, Ouardia, Ait-Si-Ali, Slimane, Akematsu, Takahiko, Akira, Shizuo, Al-Younes, Hesham M., Al-Zeer, Munir A., Albert, Matthew L., Albin, Roger L., Alegre-Abarrategui, Javier, Aleo, Maria Francesca, Alirezaei, Mehrdad, Almasan, Alexandru, Almonte-Becerril, Maylin, Amano, Atsuo, Amaravadi, Ravi, Amarnath, Shoba, Amer, Amal O., Andrieu-Abadie, Nathalie, Anantharam, Vellareddy, Ann, David K., Anoopkumar-Dukie, Shailendra, Aoki, Hiroshi, Apostolova, Nadezda, Arancia, Giuseppe, Aris, John P., Asanuma, Katsuhiko, Asare, Nana Y. O., Ashida, Hisashi, Askanas, Valerie, Askew, David S., Auberger, Patrick, Baba, Misuzu, Backues, Steven K., Baehrecke, Eric H., Bahr, Ben A., Bai, Xue-Yuan, Bailly, Yannick, Baiocchi, Robert, Baldini, Giulia, Balduini, Walter, Ballabio, Andrea, Bamber, Bruce A., Bampton, Edward T. W., Banhegyi, Gabor, Bartholomew, Clinton R., Bassham, Diane C., Bast, Robert C. Jr, Batoko, Henri, Bay, Boon-Huat, Beau, Isabelle, Bechet, Daniel M., Begley, Thomas J., Behl, Christian, Behrends, Christian, Bekri, Soumeya, Bellaire, Bryan, Bendall, Linda J., Benetti, Luca, Berliocchi, Laura, Bernardi, Henri, Bernassola, Francesca, Besteiro, Sebastien, Bhatia-Kissova, Ingrid, Bi, Xiaoning, Biard-Piechaczyk, Martine, Blum, Janice S., Boise, Lawrence H., Bonaldo, Paolo, Boone, David L., Bornhauser, Beat C., Bortoluci, Karina R., Bossis, Ioannis, Bost, Frederic, Bourquin, Jean-Pierre, Boya, Patricia, Boyer-Guittaut, Michael, Bozhkov, Peter V., Brady, Nathan R., Brancolini, Claudio, Brech, Andreas, Brenman, Jay E., Brennand, Ana, Bresnick, Emery H., Brest, Patrick, Bridges, Dave, Bristol, Molly L., Brookes, Paul S., Brown, Eric J., Brumell, John H., Brunetti-Pierri, Nicola, Brunk, Ulf T., Bulman, Dennis E., Bultman, Scott J., Bultynck, Geert, Burbulla, Lena F., Bursch, Wilfried, Butchar, Jonathan P., Buzgariu, Wanda, Bydlowski, Sergio P., Cadwell, Ken, Cahova, Monika, Cai, Dongsheng, Cai, Jiyang, Cai, Qian, Calabretta, Bruno, Calvo-Garrido, Javier, Camougrand, Nadine, Campanella, Michelangelo, Campos-Salinas, Jenny, Candi, Eleonora, Cao, Lizhi, Caplan, Allan B., Carding, Simon R., Cardoso, Sandra M., Carew, Jennifer S., Carlin, Cathleen R., Carmignac, Virginie, Carneiro, Leticia A. M., Carra, Serena, Caruso, Rosario A., Casari, Giorgio, Casas, Caty, Castino, Roberta, Cebollero, Eduardo, Cecconi, Francesco, Celli, Jean, Chaachouay, Hassan, Chae, Han-Jung, Chai, Chee-Yin, Chan, David C., Chan, Edmond Y., Chang, Raymond Chuen-Chung, Che, Chi-Ming, Chen, Ching-Chow, Chen, Guang-Chao, Chen, Guo-Qiang, Chen, Min, Chen, Quan, Chen, Steve S.-L., Chen, Wenli, Chen, Xihui, Chen, Xiangmei, Chen, Xiequn, Chen, Ye-Guang, Chen, Yingyu, Chen, Yongqiang, Chen, Yu-Jen, Chen, Zhixiang, Cheng, Alan, Cheng, Christopher H. K., Cheng, Yan, Cheong, Heesun, Cheong, Jae-Ho, Cherry, Sara, Chess-Williams, Russ, Cheung, Zelda H., Chevet, Eric, Chiang, Hui-Ling, Chiarelli, Roberto, Chiba, Tomoki, Chin, Lih-Shen, Chiou, Shih-Hwa, Chisari, Francis V., Cho, Chi Hin, Cho, Dong-Hyung, Choi, Augustine M. K., Choi, Dooseok, Choi, Kyeong Sook, Choi, Mary E., Chouaib, Salem, Choubey, Divaker, Choubey, Vinay, Chu, Charleen T., Chuang, Tsung-Hsien, Chueh, Sheau-Huei, Chun, Taehoon, Chwae, Yong-Joon, Chye, Mee-Len, Ciarcia, Roberto, Ciriolo, Maria R., Clague, Michael J., Clark, Robert S. B., Clarke, Peter G. H., Clarke, Robert, Codogno, Patrice, Coller, Hilary A., Colombo, Maria I., Comincini, Sergio, Condello, Maria, Condorelli, Fabrizio, Cookson, Mark R., Coombs, Graham H., Coppens, Isabelle, Corbalan, Ramon, Cossart, Pascale, Costelli, Paola, Costes, Safia, Coto-Montes, Ana, Couve, Eduardo, Coxon, Fraser P., Cregg, James M., Crespo, Jose L., Cronje, Marianne J., Cuervo, Ana Maria, Cullen, Joseph J., Czaja, Mark J., D'Amelio, Marcello, Darfeuille-Michaud, Arlette, Davids, Lester M., Davies, Faith E., De Felici, Massimo, de Groot, John F., de Haan, Cornelis A. M., De Martino, Luisa, De Milito, Angelo, De Tata, Vincenzo, Debnath, Jayanta, Degterev, Alexei, Dehay, Benjamin, Delbridge, Lea M. D., Demarchi, Francesca, Deng, Yi Zhen, Dengjel, Jorn, Dent, Paul, Denton, Donna, Deretic, Vojo, Desai, Shyamal D., Devenish, Rodney J., Di Gioacchino, Mario, Di Paolo, Gilbert, Di Pietro, Chiara, Diaz-Araya, Guillermo, Diaz-Laviada, Ines, Diaz-Meco, Maria T., Diaz-Nido, Javier, Dikic, Ivan, Dinesh-Kumar, Savithramma P., Ding, Wen-Xing, Distelhorst, Clark W., Diwan, Abhinav, Djavaheri-Mergny, Mojgan, Dokudovskaya, Svetlana, Dong, Zheng, Dorsey, Frank C., Dosenko, Victor, Dowling, James J., Doxsey, Stephen, Dreux, Marlene, Drew, Mark E., Duan, Qiuhong, Duchosal, Michel A., Duff, Karen, Dugail, Isabelle, Durbeej, Madeleine, Duszenko, Michael, Edelstein, Charles L., Edinger, Aimee L., Egea, Gustavo, Eichinger, Ludwig, Eissa, N. 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W., Jones, Nicola L., Joseph, Bertrand, Joseph, Suresh K., Joubert, Annie M., Juhasz, Gabor, Juillerat-Jeanneret, Lucienne, Jung, Chang Hwa, Jung, Yong-Keun, Kaarniranta, Kai, Kaasik, Allen, Kabuta, Tomohiro, Kadowaki, Motoni, Kagedal, Katarina, Kamada, Yoshiaki, Kaminskyy, Vitaliy O., Kampinga, Harm H., Kanamori, Hiromitsu, Kang, Chanhee, Kang, Khong Bee, Kang, Kwang Il, Kang, Rui, Kang, Yoon-A., Kanki, Tomotake, Kanneganti, Thirumala-Devi, Kanno, Haruo, Kanthasamy, Anumantha G., Kanthasamy, Arthi, Karantza, Vassiliki, Kaushal, Gur P., Kaushik, Susmita, Kawazoe, Yoshinori, Ke, Po-Yuan, Kehrl, John H., Kelekar, Ameeta, Kerkhoff, Claus, Kessel, David H., Khalil, Hany, Kiel, Jan A. K. 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Javier, Olsen, Laura J., Olsson, Stefan, Opota, Onya, Osborne, Timothy F., Ostrander, Gary K., Otsu, Kinya, Ou, Jing-Hsiung James, Ouimet, Mireille, Overholtzer, Michael, Ozpolat, Bulent, Paganetti, Paolo, Pagnini, Ugo, Pallet, Nicolas, Palmer, Glen E., Palumbo, Camilla, Pan, Tianhong, Panaretakis, Theocharis, Pandey, Udai Bhan, Papackova, Zuzana, Papassideri, Issidora, Paris, Irmgard, Park, Junsoo, Park, Ohkmae K., Parys, Jan B., Parzych, Katherine R., Patschan, Susann, Patterson, Cam, Pattingre, Sophie, Pawelek, John M., Peng, Jianxin, Perlmutter, David H., Perrotta, Ida, Perry, George, Pervaiz, Shazib, Peter, Matthias, Peters, Godefridus J., Petersen, Morten, Petrovski, Goran, Phang, James M., Piacentini, Mauro, Pierre, Philippe, Pierrefite-Carle, Valerie, Pierron, Gerard, Pinkas-Kramarski, Ronit, Piras, Antonio, Piri, Natik, Platanias, Leonidas C., Poggeler, Stefanie, Poirot, Marc, Poletti, Angelo, Pous, Christian, Pozuelo-Rubio, Mercedes, Praetorius-Ibba, Mette, Prasad, Anil, Prescott, Mark, Priault, Muriel, Produit-Zengaffinen, Nathalie, Progulske-Fox, Ann, Proikas-Cezanne, Tassula, Przedborski, Serge, Przyklenk, Karin, Puertollano, Rosa, Puyal, Julien, Qian, Shu-Bing, Qin, Liang, Qin, Zheng-Hong, Quaggin, Susan E., Raben, Nina, Rabinowich, Hannah, Rabkin, Simon W., Rahman, Irfan, Rami, Abdelhaq, Ramm, Georg, Randall, Glenn, Randow, Felix, Rao, V. 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V., Scharl, Michael, Schatzl, Hermann M., Scheper, Wiep, Schiaffino, Stefano, Schneider, Claudio, Schneider, Marion E., Schneider-Stock, Regine, Schoenlein, Patricia V., Schorderet, Daniel F., Schuller, Christoph, Schwartz, Gary K., Scorrano, Luca, Sealy, Linda, Seglen, Per O., Segura-Aguilar, Juan, Seiliez, Iban, Seleverstov, Oleksandr, Sell, Christian, Seo, Jong Bok, Separovic, Duska, Setaluri, Vijayasaradhi, Setoguchi, Takao, Settembre, Carmine, Shacka, John J., Shanmugam, Mala, Shapiro, Irving M., Shaulian, Eitan, Shaw, Reuben J., Shelhamer, James H., Shen, Han-Ming, Shen, Wei-Chiang, Sheng, Zu-Hang, Shi, Yang, Shibuya, Kenichi, Shidoji, Yoshihiro, Shieh, Jeng-Jer, Shih, Chwen-Ming, Shimada, Yohta, Shimizu, Shigeomi, Shintani, Takahiro, Shirihai, Orian S., Shore, Gordon C., Sibirny, Andriy A., Sidhu, Stan B., Sikorska, Beata, Silva-Zacarin, Elaine C. M., Simmons, Alison, Simon, Annabella, Simon, Hans-Uwe, Simone, Cristiano, Simonsen, Anne, Sinclair, David A., Singh, Rajat, Sinha, Debasish, Sinicrope, Frank A., Sirko, Agnieszka, Siu, Parco M., Sivridis, Efthimios, Skop, Vojtech, Skulachev, Vladimir P., Slack, Ruth S., Smaili, Soraya S., Smith, Duncan R., Soengas, Maria S., Soldati, Thierry, Song, Xueqin, Sood, Anil K., Soong, Tuck Wah, Sotgia, Federica, Spector, Stephen A., Spies, Claudia D., Springer, Wolfdieter, Srinivasula, Srinivasa M., Stefanis, Leonidas, Steffan, Joan S., Stendel, Ruediger, Stenmark, Harald, Stephanou, Anastasis, Stern, Stephan T., Sternberg, Cinthya, Stork, Bjorn, Stralfors, Peter, Subauste, Carlos S., Sui, Xinbing, Sulzer, David, Sun, Jiaren, Sun, Shi-Yong, Sun, Zhi-Jun, Sung, Joseph J. 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Paul, Terada, Lance S., Terman, Alexei, Tettamanti, Gianluca, Thevissen, Karin, Thompson, Craig B., Thorburn, Andrew, Thumm, Michael, Tian, Fengfeng, Tian, Yuan, Tocchini-Valentini, Glauco, Tolkovsky, Aviva M., Tomino, Yasuhiko, Tonges, Lars, Tooze, Sharon A., Tournier, Cathy, Tower, John, Towns, Roberto, Trajkovic, Vladimir, Travassos, Leonardo H., Tsai, Ting-Fen, Tschan, Mario P., Tsubata, Takeshi, Tsung, Allan, Turk, Boris, Turner, Lorianne S., Tyagi, Suresh C., Uchiyama, Yasuo, Ueno, Takashi, Umekawa, Midori, Umemiya-Shirafuji, Rika, Unni, Vivek K., Vaccaro, Maria I., Valente, Enza Maria, Van den Berghe, Greet, van der Klei, Ida J., van Doorn, Wouter, van Dyk, Linda F., van Egmond, Marjolein, van Grunsven, Leo A., Vandenabeele, Peter, Vandenberghe, Wim P., Vanhorebeek, Ilse, Vaquero, Eva C., Velasco, Guillermo, Vellai, Tibor, Vicencio, Jose Miguel, Vierstra, Richard D., Vila, Miquel, Vindis, Cecile, Viola, Giampietro, Viscomi, Maria Teresa, Voitsekhovskaja, Olga V., von Haefen, Clarissa, Votruba, Marcela, Wada, Keiji, Wade-Martins, Richard, Walker, Cheryl L., Walsh, Craig M., Walter, Jochen, Wan, Xiang-Bo, Wang, Aimin, Wang, Chenguang, Wang, Dawei, Wang, Fan, Wang, Fen, Wang, Guanghui, Wang, Haichao, Wang, Hong-Gang, Wang, Horng-Dar, Wang, Jin, Wang, Ke, Wang, Mei, Wang, Richard C., Wang, Xinglong, Wang, Xuejun, Wang, Ying-Jan, Wang, Yipeng, Wang, Zhen, Wang, Zhigang Charles, Wang, Zhinong, Wansink, Derick G., Ward, Diane M., Watada, Hirotaka, Waters, Sarah L., Webster, Paul, Wei, Lixin, Weihl, Conrad C., Weiss, William A., Welford, Scott M., Wen, Long-Ping, Whitehouse, Caroline A., Whitton, J. 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K., Wyttenbach, Andreas, Xavier, Ramnik J., Xi, Zhijun, Xia, Pu, Xiao, Gengfu, Xie, Zhiping, Xie, Zhonglin, Xu, Da-Zhi, Xu, Jianzhen, Xu, Liang, Xu, Xiaolei, Yamamoto, Ai, Yamamoto, Akitsugu, Yamashina, Shunhei, Yamashita, Michiaki, Yan, Xianghua, Yanagida, Mitsuhiro, Yang, Dun-Sheng, Yang, Elizabeth, Yang, Jin-Ming, Yang, Shi Yu, Yang, Wannian, Yang, Wei Yuan, Yang, Zhifen, Yao, Meng-Chao, Yao, Tso-Pang, Yeganeh, Behzad, Yen, Wei-Lien, Yin, Jia-Jing, Yin, Xiao-Ming, Yoo, Ook-Joon, Yoon, Gyesoon, Yoon, Seung-Yong, Yorimitsu, Tomohiro, Yoshikawa, Yuko, Yoshimori, Tamotsu, Yoshimoto, Kohki, You, Ho Jin, Youle, Richard J., Younes, Anas, Yu, Li, Yu, Long, Yu, Seong-Woon, Yu, Wai Haung, Yuan, Zhi-Min, Yue, Zhenyu, Yun, Cheol-Heui, Yuzaki, Michisuke, Zabirnyk, Olga, Silva-Zacarin, Elaine, Zacks, David, Zacksenhaus, Eldad, Zaffaroni, Nadia, Zakeri, Zahra, Zeh, Herbert J. Rd, Zeitlin, Scott O., Zhang, Hong, Zhang, Hui-Ling, Zhang, Jianhua, Zhang, Jing-Pu, Zhang, Lin, Zhang, Long, Zhang, Ming-Yong, Zhang, Xu Dong, Zhao, Mantong, Zhao, Yi-Fang, Zhao, Ying, Zhao, Zhizhuang J., Zheng, Xiaoxiang, Zhivotovsky, Boris, Zhong, Qing, Zhou, Cong-Zhao, Zhu, Changlian, Zhu, Wei-Guo, Zhu, Xiao-Feng, Zhu, Xiongwei, Zhu, Yuangang, Zoladek, Teresa, Zong, Wei-Xing, Zorzano, Antonio, Zschocke, Jurgen, Zuckerbraun, Brian, Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Klionsky, Daniel J., Abdalla, Fabio C., Abeliovich, Hagai, Abraham, Robert T., Acevedo-Arozena, Abraham, Adeli, Khosrow, Agholme, Lotta, Agnello, Maria, Agostinis, Patrizia, Aguirre-Ghiso, Julio A., Ahn, Hyung Jun, Ait-Mohamed, Ouardia, Ait-Si-Ali, Slimane, Akematsu, Takahiko, Akira, Shizuo, Al-Younes, Hesham M., Al-Zeer, Munir A., Albert, Matthew L., Albin, Roger L., Alegre-Abarrategui, Javier, Aleo, Maria Francesca, Alirezaei, Mehrdad, Almasan, Alexandru, Almonte-Becerril, Maylin, Amano, Atsuo, Amaravadi, Ravi, Amarnath, Shoba, Amer, Amal O., Andrieu-Abadie, Nathalie, Anantharam, Vellareddy, Ann, David K., Anoopkumar-Dukie, Shailendra, Aoki, Hiroshi, Apostolova, Nadezda, Arancia, Giuseppe, Aris, John P., Asanuma, Katsuhiko, Asare, Nana Y. O., Ashida, Hisashi, Askanas, Valerie, Askew, David S., Auberger, Patrick, Baba, Misuzu, Backues, Steven K., Baehrecke, Eric H., Bahr, Ben A., Bai, Xue-Yuan, Bailly, Yannick, Baiocchi, Robert, Baldini, Giulia, Balduini, Walter, Ballabio, Andrea, Bamber, Bruce A., Bampton, Edward T. W., Banhegyi, Gabor, Bartholomew, Clinton R., Bassham, Diane C., Bast, Robert C. Jr, Batoko, Henri, Bay, Boon-Huat, Beau, Isabelle, Bechet, Daniel M., Begley, Thomas J., Behl, Christian, Behrends, Christian, Bekri, Soumeya, Bellaire, Bryan, Bendall, Linda J., Benetti, Luca, Berliocchi, Laura, Bernardi, Henri, Bernassola, Francesca, Besteiro, Sebastien, Bhatia-Kissova, Ingrid, Bi, Xiaoning, Biard-Piechaczyk, Martine, Blum, Janice S., Boise, Lawrence H., Bonaldo, Paolo, Boone, David L., Bornhauser, Beat C., Bortoluci, Karina R., Bossis, Ioannis, Bost, Frederic, Bourquin, Jean-Pierre, Boya, Patricia, Boyer-Guittaut, Michael, Bozhkov, Peter V., Brady, Nathan R., Brancolini, Claudio, Brech, Andreas, Brenman, Jay E., Brennand, Ana, Bresnick, Emery H., Brest, Patrick, Bridges, Dave, Bristol, Molly L., Brookes, Paul S., Brown, Eric J., Brumell, John H., Brunetti-Pierri, Nicola, Brunk, Ulf T., Bulman, Dennis E., Bultman, Scott J., Bultynck, Geert, Burbulla, Lena F., Bursch, Wilfried, Butchar, Jonathan P., Buzgariu, Wanda, Bydlowski, Sergio P., Cadwell, Ken, Cahova, Monika, Cai, Dongsheng, Cai, Jiyang, Cai, Qian, Calabretta, Bruno, Calvo-Garrido, Javier, Camougrand, Nadine, Campanella, Michelangelo, Campos-Salinas, Jenny, Candi, Eleonora, Cao, Lizhi, Caplan, Allan B., Carding, Simon R., Cardoso, Sandra M., Carew, Jennifer S., Carlin, Cathleen R., Carmignac, Virginie, Carneiro, Leticia A. M., Carra, Serena, Caruso, Rosario A., Casari, Giorgio, Casas, Caty, Castino, Roberta, Cebollero, Eduardo, Cecconi, Francesco, Celli, Jean, Chaachouay, Hassan, Chae, Han-Jung, Chai, Chee-Yin, Chan, David C., Chan, Edmond Y., Chang, Raymond Chuen-Chung, Che, Chi-Ming, Chen, Ching-Chow, Chen, Guang-Chao, Chen, Guo-Qiang, Chen, Min, Chen, Quan, Chen, Steve S.-L., Chen, Wenli, Chen, Xihui, Chen, Xiangmei, Chen, Xiequn, Chen, Ye-Guang, Chen, Yingyu, Chen, Yongqiang, Chen, Yu-Jen, Chen, Zhixiang, Cheng, Alan, Cheng, Christopher H. K., Cheng, Yan, Cheong, Heesun, Cheong, Jae-Ho, Cherry, Sara, Chess-Williams, Russ, Cheung, Zelda H., Chevet, Eric, Chiang, Hui-Ling, Chiarelli, Roberto, Chiba, Tomoki, Chin, Lih-Shen, Chiou, Shih-Hwa, Chisari, Francis V., Cho, Chi Hin, Cho, Dong-Hyung, Choi, Augustine M. K., Choi, Dooseok, Choi, Kyeong Sook, Choi, Mary E., Chouaib, Salem, Choubey, Divaker, Choubey, Vinay, Chu, Charleen T., Chuang, Tsung-Hsien, Chueh, Sheau-Huei, Chun, Taehoon, Chwae, Yong-Joon, Chye, Mee-Len, Ciarcia, Roberto, Ciriolo, Maria R., Clague, Michael J., Clark, Robert S. B., Clarke, Peter G. H., Clarke, Robert, Codogno, Patrice, Coller, Hilary A., Colombo, Maria I., Comincini, Sergio, Condello, Maria, Condorelli, Fabrizio, Cookson, Mark R., Coombs, Graham H., Coppens, Isabelle, Corbalan, Ramon, Cossart, Pascale, Costelli, Paola, Costes, Safia, Coto-Montes, Ana, Couve, Eduardo, Coxon, Fraser P., Cregg, James M., Crespo, Jose L., Cronje, Marianne J., Cuervo, Ana Maria, Cullen, Joseph J., Czaja, Mark J., D'Amelio, Marcello, Darfeuille-Michaud, Arlette, Davids, Lester M., Davies, Faith E., De Felici, Massimo, de Groot, John F., de Haan, Cornelis A. M., De Martino, Luisa, De Milito, Angelo, De Tata, Vincenzo, Debnath, Jayanta, Degterev, Alexei, Dehay, Benjamin, Delbridge, Lea M. D., Demarchi, Francesca, Deng, Yi Zhen, Dengjel, Jorn, Dent, Paul, Denton, Donna, Deretic, Vojo, Desai, Shyamal D., Devenish, Rodney J., Di Gioacchino, Mario, Di Paolo, Gilbert, Di Pietro, Chiara, Diaz-Araya, Guillermo, Diaz-Laviada, Ines, Diaz-Meco, Maria T., Diaz-Nido, Javier, Dikic, Ivan, Dinesh-Kumar, Savithramma P., Ding, Wen-Xing, Distelhorst, Clark W., Diwan, Abhinav, Djavaheri-Mergny, Mojgan, Dokudovskaya, Svetlana, Dong, Zheng, Dorsey, Frank C., Dosenko, Victor, Dowling, James J., Doxsey, Stephen, Dreux, Marlene, Drew, Mark E., Duan, Qiuhong, Duchosal, Michel A., Duff, Karen, Dugail, Isabelle, Durbeej, Madeleine, Duszenko, Michael, Edelstein, Charles L., Edinger, Aimee L., Egea, Gustavo, Eichinger, Ludwig, Eissa, N. Tony, Ekmekcioglu, Suhendan, El-Deiry, Wafik S., Elazar, Zvulun, Elgendy, Mohamed, Ellerby, Lisa M., Eng, Kai Er, Engelbrecht, Anna-Mart, Engelender, Simone, Erenpreisa, Jekaterina, Escalante, Ricardo, Esclatine, Audrey, Eskelinen, Eeva-Liisa, Espert, Lucile, Espina, Virginia, Fan, Huizhou, Fan, Jia, Fan, Qi-Wen, Fan, Zhen, Fang, Shengyun, Fang, Yongqi, Fanto, Manolis, Fanzani, Alessandro, Farkas, Thomas, Farre, Jean-Claude, Faure, Mathias, Fechheimer, Marcus, Feng, Carl G., Feng, Jian, Feng, Qili, Feng, Youji, Fesus, Laszlo, Feuer, Ralph, Figueiredo-Pereira, Maria E., Fimia, Gian Maria, Fingar, Diane C., Finkbeiner, Steven, Finkel, Toren, Finley, Kim D., Fiorito, Filomena, Fisher, Edward A., Fisher, Paul B., Flajolet, Marc, Florez-McClure, Maria L., Florio, Salvatore, Fon, Edward A., Fornai, Francesco, Fortunato, Franco, Fotedar, Rati, Fowler, Daniel H., Fox, Howard S., Franco, Rodrigo, Frankel, Lisa B., Fransen, Marc, Fuentes, Jose M., Fueyo, Juan, Fujii, Jun, Fujisaki, Kozo, Fujita, Eriko, Fukuda, Mitsunori, Furukawa, Ruth H., Gaestel, Matthias, Gailly, Philippe, Gajewska, Malgorzata, Galliot, Brigitte, Galy, Vincent, Ganesh, Subramaniam, Ganetzky, Barry, Ganley, Ian G., Gao, Fen-Biao, Gao, George F., Gao, Jinming, Garcia, Lorena, Garcia-Manero, Guillermo, Garcia-Marcos, Mikel, Garmyn, Marjan, Gartel, Andrei L., Gatti, Evelina, Gautel, Mathias, Gawriluk, Thomas R., Gegg, Matthew E., Geng, Jiefei, Germain, Marc, Gestwicki, Jason E., Gewirtz, David A., Ghavami, Saeid, Ghosh, Pradipta, Giammarioli, Anna M., Giatromanolaki, Alexandra N., Gibson, Spencer B., Gilkerson, Robert W., Ginger, Michael L., Ginsberg, Henry N., Golab, Jakub, Goligorsky, Michael S., Golstein, Pierre, Gomez-Manzano, Candelaria, Goncu, Ebru, Gongora, Celine, Gonzalez, Claudio D., Gonzalez, Ramon, Gonzalez-Estevez, Cristina, Gonzalez-Polo, Rosa Ana, Gonzalez-Rey, Elena, Gorbunov, Nikolai V., Gorski, Sharon, Goruppi, Sandro, Gottlieb, Roberta A., Gozuacik, Devrim, Granato, Giovanna Elvira, Grant, Gary D., Green, Kim N., Gregorc, Ales, Gros, Frederic, Grose, Charles, Grunt, Thomas W., Gual, Philippe, Guan, Jun-Lin, Guan, Kun-Liang, Guichard, Sylvie M., Gukovskaya, Anna S., Gukovsky, Ilya, Gunst, Jan, Gustafsson, Asa B., Halayko, Andrew J., Hale, Amber N., Halonen, Sandra K., Hamasaki, Maho, Han, Feng, Han, Ting, Hancock, Michael K., Hansen, Malene, Harada, Hisashi, Harada, Masaru, Hardt, Stefan E., Harper, J. 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W., Jones, Nicola L., Joseph, Bertrand, Joseph, Suresh K., Joubert, Annie M., Juhasz, Gabor, Juillerat-Jeanneret, Lucienne, Jung, Chang Hwa, Jung, Yong-Keun, Kaarniranta, Kai, Kaasik, Allen, Kabuta, Tomohiro, Kadowaki, Motoni, Kagedal, Katarina, Kamada, Yoshiaki, Kaminskyy, Vitaliy O., Kampinga, Harm H., Kanamori, Hiromitsu, Kang, Chanhee, Kang, Khong Bee, Kang, Kwang Il, Kang, Rui, Kang, Yoon-A., Kanki, Tomotake, Kanneganti, Thirumala-Devi, Kanno, Haruo, Kanthasamy, Anumantha G., Kanthasamy, Arthi, Karantza, Vassiliki, Kaushal, Gur P., Kaushik, Susmita, Kawazoe, Yoshinori, Ke, Po-Yuan, Kehrl, John H., Kelekar, Ameeta, Kerkhoff, Claus, Kessel, David H., Khalil, Hany, Kiel, Jan A. K. W., Kiger, Amy A., Kihara, Akio, Kim, Deok Ryong, Kim, Do-Hyung, Kim, Dong-Hou, Kim, Eun-Kyoung, Kim, Hyung-Ryong, Kim, Jae-Sung, Kim, Jeong Hun, Kim, Jin Cheon, Kim, John K., Kim, Peter K., Kim, Seong Who, Kim, Yong-Sun, Kim, Yonghyun, Kimchi, Adi, Kimmelman, Alec C., King, Jason S., Kinsella, Timothy J., Kirkin, Vladimir, Kirshenbaum, Lorrie A., Kitamoto, Katsuhiko, Kitazato, Kaio, Klein, Ludger, Klimecki, Walter T., Klucken, Jochen, Knecht, Erwin, Ko, Ben C. B., Koch, Jan C., Koga, Hiroshi, Koh, Jae-Young, Koh, Young Ho, Koike, Masato, Komatsu, Masaaki, Kominami, Eiki, Kong, Hee Jeong, Kong, Wei-Jia, Korolchuk, Viktor I., Kotake, Yaichiro, Koukourakis, Michael I., Kouri Flores, Juan B., Kovacs, Attila L., Kraft, Claudine, Krainc, Dimitri, Kramer, Helmut, Kretz-Remy, Carole, Krichevsky, Anna M., Kroemer, Guido, Krüger, Rejko, Krut, Oleg, Ktistakis, Nicholas T., Kuan, Chia-Yi, Kucharczyk, Roza, Kumar, Ashok, Kumar, Raj, Kumar, Sharad, Kundu, Mondira, Kung, Hsing-Jien, Kurz, Tino, Kwon, Ho Jeong, La Spada, Albert R., Lafont, Frank, Lamark, Trond, Landry, Jacques, Lane, Jon D., Lapaquette, Pierre, Laporte, Jocelyn F., Laszlo, Lajos, Lavandero, Sergio, Lavoie, Josee N., Layfield, Robert, Lazo, Pedro A., Le, Weidong, Le Cam, Laurent, Ledbetter, Daniel J., Lee, Alvin J. X., Lee, Byung-Wan, Lee, Gyun Min, Lee, Jongdae, Lee, Ju-Hyun, Lee, Michael, Lee, Myung-Shik, Lee, Sug Hyung, Leeuwenburgh, Christiaan, Legembre, Patrick, Legouis, Renaud, Lehmann, Michael, Lei, Huan-Yao, Lei, Qun-Ying, Leib, David A., Leiro, Jose, Lemasters, John J., Lemoine, Antoinette, Lesniak, Maciej S., Lev, Dina, Levenson, Victor V., Levine, Beth, Levy, Efrat, Li, Faqiang, Li, Jun-Lin, Li, Lian, Li, Sheng, Li, Weijie, Li, Xue-Jun, Li, Yan-Bo, Li, Yi-Ping, Liang, Chengyu, Liang, Qiangrong, Liao, Yung-Feng, Liberski, Pawel P., Lieberman, Andrew, Lim, Hyunjung J., Lim, Kah-Leong, Lim, Kyu, Lin, Chiou-Feng, Lin, Fu-Cheng, Lin, Jian, Lin, Jiandie D., Lin, Kui, Lin, Wan-Wan, Lin, Weei-Chin, Lin, Yi-Ling, Linden, Rafael, Lingor, Paul, Lippincott-Schwartz, Jennifer, Lisanti, Michael P., Liton, Paloma B., Liu, Bo, Liu, Chun-Feng, Liu, Kaiyu, Liu, Leyuan, Liu, Qiong A., Liu, Wei, Liu, Young-Chau, Liu, Yule, Lockshin, Richard A., Lok, Chun-Nam, Lonial, Sagar, Loos, Benjamin, Lopez-Berestein, Gabriel, Lopez-Otin, Carlos, Lossi, Laura, Lotze, Michael T., Low, Peter, Lu, Binfeng, Lu, Bingwei, Lu, Bo, Lu, Zhen, Luciano, Frederic, Lukacs, Nicholas W., Lund, Anders H., Lynch-Day, Melinda A., Ma, Yong, Macian, Fernando, MacKeigan, Jeff P., Macleod, Kay F., Madeo, Frank, Maiuri, Luigi, Maiuri, Maria Chiara, Malagoli, Davide, Malicdan, May Christine V., Malorni, Walter, Man, Na, Mandelkow, Eva-Maria, Manon, Stephen, Manov, Irena, Mao, Kai, Mao, Xiang, Mao, Zixu, Marambaud, Philippe, Marazziti, Daniela, Marcel, Yves L., Marchbank, Katie, Marchetti, Piero, Marciniak, Stefan J., Marcondes, Mateus, Mardi, Mohsen, Marfe, Gabriella, Marino, Guillermo, Markaki, Maria, Marten, Mark R., Martin, Seamus J., Martinand-Mari, Camille, Martinet, Wim, Martinez-Vicente, Marta, Masini, Matilde, Matarrese, Paola, Matsuo, Saburo, Matteoni, Raffaele, Mayer, Andreas, Mazure, Nathalie M., McConkey, David J., McConnell, Melanie J., McDermott, Catherine, McDonald, Christine, McInerney, Gerald M., McKenna, Sharon L., McLaughlin, Bethann, McLean, Pamela J., McMaster, Christopher R., McQuibban, G. 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- Abstract
In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused o
- Published
- 2012
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47. Guidelines for the use and interpretation of assays for monitoring autophagy
- Author
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Liu, Kaiyu, Liu, Leyuan, Liu, Qiong A, Liu, Wei, Liu, Young-Chau, Liu, Yule, Lockshin, Richard A, Lok, Chun-Nam, Lonial, Sagar, Loos, Benjamin, Lopez-Berestein, Gabriel, López-Otín, Carlos, Lossi, Laura, Lotze, Michael T, Lőw, Peter, Lu, Binfeng, Lu, Bingwei, Lu, Bo, Lu, Zhen, Luciano, Frédéric, Lukacs, Nicholas W, Lund, Anders H, Lynch-Day, Melinda A, Ma, Yong, Macian, Fernando, MacKeigan, Jeff P, Macleod, Kay F, Madeo, Frank, Maiuri, Luigi, Maiuri, Maria Chiara, Malagoli, Davide, Malicdan, May Christine V, Malorni, Walter, Man, Na, Mandelkow, Eva-Maria, Manon, Stéphen, Manov, Irena, Mao, Kai, Mao, Xiang, Mao, Zixu, Marambaud, Philippe, Marazziti, Daniela, Marcel, Yves L, Marchbank, Katie, Marchetti, Piero, Marciniak, Stefan J, Marcondes, Mateus, Mardi, Mohsen, Marfe, Gabriella, Mariño, Guillermo, Markaki, Maria, Marten, Mark R, Martin, Seamus J, Martinand-Mari, Camille, Martinet, Wim, Martinez-Vicente, Marta, Masini, Matilde, Matarrese, Paola, Matsuo, Saburo, Matteoni, Raffaele, Mayer, Andreas, Mazure, Nathalie M, McConkey, David J, McConnell, Melanie J, McDermott, Catherine, McDonald, Christine, McInerney, Gerald M, McKenna, Sharon L, McLaughlin, BethAnn, McLean, Pamela J, McMaster, Christopher R, McQuibban, G Angus, Meijer, Alfred J, Meisler, Miriam H, Meléndez, Alicia, Melia, Thomas J, Melino, Gerry, Mena, Maria A, Menendez, Javier A, Menna-Barreto, Rubem F S, Menon, Manoj B, Menzies, Fiona M, Mercer, Carol A, Merighi, Adalberto, Merry, Diane E, Meschini, Stefania, Meyer, Christian G, Meyer, Thomas F, Miao, Chao-Yu, Miao, Jun-Ying, Michels, Paul A M, Michiels, Carine, Mijaljica, Dalibor, Milojkovic, Ana, Minucci, Saverio, Miracco, Clelia, Miranti, Cindy K, Mitroulis, Ioannis, Miyazawa, Keisuke, Mizushima, Noboru, Mograbi, Baharia, Mohseni, Simin, Molero, Xavier, Mollereau, Bertrand, Mollinedo, Faustino, Momoi, Takashi, Monastyrska, Iryna, Monick, Martha M, Monteiro, Mervyn J, Moore, Michael N, Mora, Rodrigo, Moreau, Kevin, Moreira, Paula I, Moriyasu, Yuji, Moscat, Jorge, Mostowy, Serge, Mottram, Jeremy C, Motyl, Tomasz, Moussa, Charbel E-H, Müller, Sylke, Muller, Sylviane, Münger, Karl, Münz, Christian, Murphy, Leon O, Murphy, Maureen E, Musarò, Antonio, Mysorekar, Indira, Nagata, Eiichiro, Nagata, Kazuhiro, Nahimana, Aimable, Nair, Usha, Nakagawa, Toshiyuki, Nakahira, Kiichi, Nakano, Hiroyasu, Nakatogawa, Hitoshi, Nanjundan, Meera, Naqvi, Naweed I, Narendra, Derek P, Narita, Masashi, Navarro, Miguel, Nawrocki, Steffan T, Nazarko, Taras Y, Nemchenko, Andriy, Netea, Mihai G, Neufeld, Thomas P, Ney, Paul A, Nezis, Ioannis P, Nguyen, Huu Phuc, Nie, Daotai, Nishino, Ichizo, Nislow, Corey, Nixon, Ralph A, Noda, Takeshi, Noegel, Angelika A, Nogalska, Anna, Noguchi, Satoru, Notterpek, Lucia, Novak, Ivana, Nozaki, Tomoyoshi, Nukina, Nobuyuki, Nürnberger, Thorsten, Nyfeler, Beat, Obara, Keisuke, Oberley, Terry D, Oddo, Salvatore, Ogawa, Michinaga, Ohashi, Toya, Okamoto, Koji, Oleinick, Nancy L, Oliver, F Javier, Olsen, Laura J, Olsson, Stefan, Opota, Onya, Osborne, Timothy F, Ostrander, Gary K, Otsu, Kinya, Ou, Jing-hsiung James, Ouimet, Mireille, Overholtzer, Michael, Ozpolat, Bulent, Paganetti, Paolo, Pagnini, Ugo, Pallet, Nicolas, Palmer, Glen E, Palumbo, Camilla, Pan, Tianhong, Panaretakis, Theocharis, Pandey, Udai Bhan, Papackova, Zuzana, Papassideri, Issidora, Paris, Irmgard, Park, Junsoo, Park, Ohkmae K, Parys, Jan B, Parzych, Katherine R, Patschan, Susann, Patterson, Cam, Pattingre, Sophie, Pawelek, John M, Peng, Jianxin, Perlmutter, David H, Perrotta, Ida, Perry, George, Pervaiz, Shazib, Peter, Matthias, Peters, Godefridus J, Petersen, Morten, Petrovski, Goran, Phang, James M, Piacentini, Mauro, Pierre, Philippe, Pierrefite-Carle, Valérie, Pierron, Gérard, Pinkas-Kramarski, Ronit, Piras, Antonio, Piri, Natik, Platanias, Leonidas C, Pöggeler, Stefanie, Poirot, Marc, Poletti, Angelo, Poüs, Christian, Pozuelo-Rubio, Mercedes, Prætorius-Ibba, Mette, Prasad, Anil, Prescott, Mark, Priault, Muriel, Produit-Zengaffinen, 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Yoshikawa, Yuko, Yoshimori, Tamotsu, Yoshimoto, Kohki, You, Ho Jin, Youle, Richard J, Younes, Anas, Yu, Li, Yu, Long, Yu, Seong-Woon, Yu, Wai Haung, Yuan, Zhi-Min, Yue, Zhenyu, Yun, Cheol-Heui, Yuzaki, Michisuke, Zabirnyk, Olga, Silva-Zacarin, Elaine, Zacks, David, Zacksenhaus, Eldad, Zaffaroni, Nadia, Zakeri, Zahra, Zeh, Herbert J, Zeitlin, Scott O, Zhang, Hong, Zhang, Hui-Ling, Zhang, Jianhua, Zhang, Jing-Pu, Zhang, Lin, Zhang, Long, Zhang, Ming-Yong, Zhang, Xu Dong, Zhao, Mantong, Zhao, Yi-Fang, Zhao, Ying, Zhao, Zhizhuang J, Zheng, Xiaoxiang, Zhivotovsky, Boris, Zhong, Qing, Zhou, Cong-Zhao, Zhu, Changlian, Zhu, Wei-Guo, Zhu, Xiao-Feng, Zhu, Xiongwei, Zhu, Yuangang, Zoladek, Teresa, Zong, Wei-Xing, Zorzano, Antonio, Zschocke, Jürgen, and Zuckerbraun, Brian
- Abstract
In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused o
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- 2012
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48. Converging environmental and genetic pathways in the pathogenesis of Parkinson's disease.
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Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Burbulla, Lena F., Krüger, Rejko, Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Burbulla, Lena F., and Krüger, Rejko
- Abstract
As a prototypic neurodegenerative disorder Parkinson's disease (PD) is characterized by the progressive loss of specific neuronal subpopulations leading to a late-onset movement disorder. Based on familial forms of PD, to date a significant number of genes were identified that allowed first insight into the molecular pathogenesis of this common movement disorder. These pathways include impaired protein degradation and subsequent aggregation within neuronal cells and impaired mitochondrial function followed by energy depletion due to oxidative stress leading to cell death. The respective disease models were supported by pathoanatomical and biochemical findings in brains of sporadic PD patients without apparent genetic contribution to pathogenesis. Indeed recent genetic and epidemiological studies hint to a complex interplay of genetic susceptibility factors and environmental risk factors to converge to processes of pathological protein accumulation and mitochondrial damage that trigger neurodegeneration in PD. Therefore large-scale geneticoepidemiological studies combining genetic whole genome approaches with a detailed ascertainment of environmental exposures are expected to provide important clues to decipher the complexity of neurodegeneration of this most frequent neurodegenerative movement disorder.
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- 2011
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49. Dissecting the role of the mitochondrial chaperone mortalin in Parkinson's disease: functional impact of disease-related variants on mitochondrial homeostasis.
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Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Burbulla, Lena F., Schelling, Carina, Kato, Hiroki, Rapaport, Doron, Woitalla, Dirk, Schiesling, Carola, Schulte, Claudia, Sharma, Manu, Illig, Thomas, Bauer, Peter, Jung, Stephan, Nordheim, Alfred, Schols, Ludger, Riess, Olaf, Krüger, Rejko, Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Burbulla, Lena F., Schelling, Carina, Kato, Hiroki, Rapaport, Doron, Woitalla, Dirk, Schiesling, Carola, Schulte, Claudia, Sharma, Manu, Illig, Thomas, Bauer, Peter, Jung, Stephan, Nordheim, Alfred, Schols, Ludger, Riess, Olaf, and Krüger, Rejko
- Abstract
The mitochondrial chaperone mortalin has been linked to neurodegeneration in Parkinson's disease (PD) based on reduced protein levels in affected brain regions of PD patients and its interaction with the PD-associated protein DJ-1. Recently, two amino acid exchanges in the ATPase domain (R126W) and the substrate-binding domain (P509S) of mortalin were identified in Spanish PD patients. Here, we identified a separate and novel variant (A476T) in the substrate-binding domain of mortalin in German PD patients. To define a potential role as a susceptibility factor in PD, we characterized the functions of all three variants in different cellular models. In vitro import assays revealed normal targeting of all mortalin variants. In neuronal and non-neuronal human cell lines, the disease-associated variants caused a mitochondrial phenotype of increased reactive oxygen species and reduced mitochondrial membrane potential, which were exacerbated upon proteolytic stress. These functional impairments correspond with characteristic alterations of the mitochondrial network in cells overexpressing mutant mortalin compared with wild-type (wt), which were confirmed in fibroblasts from a carrier of the A476T variant. In line with a loss of function hypothesis, knockdown of mortalin in human cells caused impaired mitochondrial function that was rescued by wt mortalin, but not by the variants. Our genetic and functional studies of novel disease-associated variants in the mortalin gene define a loss of mortalin function, which causes impaired mitochondrial function and dynamics. Our results support the role of this mitochondrial chaperone in neurodegeneration and underscore the concept of impaired mitochondrial protein quality control in PD.
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- 2010
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50. Balance is the challenge--the impact of mitochondrial dynamics in Parkinson's disease.
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Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Burbulla, Lena F., Krebiehl, Guido, Krüger, Rejko, Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Burbulla, Lena F., Krebiehl, Guido, and Krüger, Rejko
- Abstract
Impaired mitochondrial function has been implicated in neurodegeneration in Parkinson's disease (PD) based on biochemical and pathoanatomical studies in brains of PD patients. This observation was further substantiated by the identification of exogenic toxins, i.e. complex I inhibitors that directly affect mitochondrial energy metabolism and cause Parkinsonism in humans and various animal models. Recently, insights into the underlying molecular signalling pathways leading to alterations in mitochondrial homeostasis were gained based on the functional characterization of mitoprotective genes identified in rare forms of inherited PD. Using in vitro and in vivo loss of function models of the Parkin, PINK1, DJ-1 and Omi/HtrA2 gene, the emerging field of mitochondrial dynamics in PD was established as being critical for the maintenance of mitochondrial function in neurons. This underscored the concept that mitochondria are highly dynamic organelles, which are tightly regulated to continuously adapt shape to functional and anatomical requirements during axonal transport, synaptic signalling, organelle degradation and cellular energy supply. The dissection of pathways involved in mitochondrial quality control clearly established the PINK1/Parkin-pathway in the clearance of dysfunctional mitochondria by autophagy and hints to a complex interplay between PD-associated proteins acting at the mitochondrial interface. The elucidation of this mitoprotective signalling network may help to define novel therapeutic targets for PD via molecular modelling of mitochondria and/or pharmacological modulation of mitochondrial dynamics.
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- 2010
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