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1. Possibilities to generation of optical non-diffracting beams by holographic metasurfaces using surface impedance

Author

Fernandez, Santiago R. C. and Gesualdi, Marcos R. R.

Subjects
Physics - Optics
Abstract

In this work, we present the computational simulations of holographic metasurfaces to generation of the optical non-diffracting beams. The metasurfaces are designed by the holographic technique and the computer-generated holograms (CGHs) of optical non-diffracting beams are generated computationally. These holographic metasurfaces (HMS) are obtained by modeling a periodic lattice of metallic patches on dielectric substrates with sub-wavelength dimensions, where each one of those unit cells change the phase of the incoming wave. We use the surface impedance (Z) to control the phase of the electromagnetic wave through the metasurface in each unit cell. The sub-wavelength dimensions guarantees that the effective medium theory is fulfilled. The results is according to the predicted by non-diffracting beams theory. These results are important given the possibilities of applications in optical tweezers, optics communications, optical metrology, 3D imaging, and others in optics and photonics, Comment: 19 pages, 22 figures. arXiv admin note: substantial text overlap with arXiv:1908.09624

Published
2020

2. Holographic metasurfaces simulations applied to realization of non-diffracting waves in the microwave regime

Author

Fernandez, Santiago R. C. and Gesualdi, Marcos R. R.

Subjects
Physics - Classical Physics
Abstract

In this work, we present the computational realization of holographic metasurfaces to generation of the non-diffracting waves. These holographic metasurfaces (HMS) are simulated by modeling a periodic lattice of metallic patches on dielectric substrates with sub-wavelength dimensions, where each one of those unit cells alter the phase of the incoming wave. We use the surface impedance (Z) to control the phase of the electromagnetic wave through the metasurface in each unit cell. The sub-wavelength dimensions guarantees that the effective medium theory is fulfilled. The metasurfaces are designed by the holographic technique and the computer-generated holograms (CGHs) of non-diffracting waves are generated and reproduced using such HMS in the microwave regime. The results is according to the theoretically predicted by non-diffracting wave theory. These results are important given the possibilities of applications of these types of electromagnetic waves in several areas of telecommunications and bioengineering., Comment: 16 pages, 15 figures

Published
2019

3. Long-Term Outcomes of Perioperative Versus Neoadjuvant Chemotherapy for Resectable Colorectal Liver Metastases: An International Multicentre Propensity-Score Matched Analysis with Stratification by Contemporary Risk-Scoring

Author

Di Martino M, Primavesi F, Syn N, Dorcaratto D, de la Hoz Rodriguez A, Dupre A, Piardi T, Rhaiem R, Blanco Fernandez G, de Armas Conde N, Rodriguez Sanjuan J, Fernandez Santiago R, Fernandez-Moreno M, Ferret G, Lopez Ben S, Suarez Munoz M, Perez-Alonso A, Koh Y, Jones R, and Martin-Perez E

Abstract

BACKGROUND: There is still debate regarding the principal role and ideal timing of perioperative chemotherapy (CTx) for patients with upfront resectable colorectal liver metastases (CRLM). This study assesses long-term oncological outcomes in patients receiving neoadjuvant CTx only versus those receiving neoadjuvant combined with adjuvant therapy (perioperative CTx).; METHODS: International multicentre retrospective analysis of patients with CRLM undergoing liver resection between 2010 and 2015. Characteristics and outcomes were compared before and after propensity score matching (PSM). Primary endpoints were long-term oncological outcomes, such as recurrence-free survival (RFS) and overall survival (OS). Furthermore, stratification by the tumour burden score (TBS) was applied.; RESULTS: Of 967 patients undergoing hepatectomy, 252 were analysed, with a median follow-up of 45 months. The unmatched comparison revealed a bias towards patients with neoadjuvant CTx presenting with more high-risk patients (p = 0.045) and experiencing increased postoperative complications =Clavien-Dindo III (20.9% vs. 8%, p = 0.003). Multivariable analysis showed that perioperative CTx was associated with significantly improved RFS (hazard ratio [HR] 0.579, 95% confidence interval [CI] 0.420-0.800, p = 0.001) and OS (HR 0.579, 95% CI 0.403-0.834, p = 0.003). After PSM (n = 180 patients), the two groups were comparable regarding baseline characteristics. The perioperative CTx group presented with a significantly prolonged RFS (HR 0.53, 95% CI 0.37-0.76, p = 0.007) and OS (HR 0.58, 95% CI 0.38-0.87, p = 0.010) in both low and high TBS patients.; CONCLUSIONS: When patients after resection of CRLM are able to tolerate additional postoperative CTx, a perioperative strategy demonstrates increased RFS and OS in comparison with neoadjuvant CTx only in both low and high-risk situations. © 2022. Society of Surgical Oncology.

Published
2022

4. ASO Visual Abstract: Long-Term Outcomes of Perioperative versus Neoadjuvant Chemotherapy for Resectable Colorectal Liver Metastases-An International Multicenter Propensity-Score Matched Analysis with Stratification by Contemporary Risk Scoring

Author

Di Martino M, Primavesi F, Syn N, Dorcaratto D, de la Hoz Rodriguez A, Dupre A, Piardi T, Rhaiem R, Blanco Fernandez G, de Armas Conde N, Rodriguez Sanjuan J, Fernandez Santiago R, Fernandez-Moreno M, Ferret G, Lopez Ben S, Suarez Munoz M, Perez-Alonso A, Koh Y, Jones R, and Martin-Perez E

Published
2022

5. Perioperative chemotherapy versus surgery alone for resectable colorectal liver metastases: an international multicentre propensity score matched analysis on long-term outcomes according to established prognostic risk scores

Author

Di Martino M, Primavesi F, Syn N, Dorcaratto D, de la Hoz Rodriguez A, Dupre A, Piardi T, Rhaiem R, Blanco Fernandez G, Prada Villaverde A, Rodriguez Sanjuan J, Fernandez Santiago R, Fernandez-Moreno M, Ferret G, Lopez Ben S, Suarez Munoz M, Perez-Alonso A, Koh Y, Jones R, and Martin-Perez E

Abstract

BACKGROUND: There is still uncertainty regarding the role of perioperative chemotherapy (CTx) in patients with resectable colorectal liver metastases (CRLM), especially in those with a low-risk of recurrence. METHODS: Multicentre retrospective analysis of patients with CRLM undergoing liver resection between 2010-2015. Patients were divided into two groups according to whether they received perioperative CTx or not and were compared using propensity score matching (PSM) analysis. Then, they were stratified according to prognostic risk scores, including: Clinical Risk Score (CRS), Tumour Burden Score (TBS) and Genetic And Morphological Evaluation (GAME) score. RESULTS: The study included 967 patients with a median follow-up of 68 months. After PSM analysis, patients with perioperative CTx presented prolonged overall survival (OS) in comparison with the surgery alone group (82.8 vs 52.5 months, p = 0.017). On multivariable analysis perioperative CTx was an independent predictor of increased OS (HR 0.705, 95%CI 0.705-0.516, p = 0.029). The benefits of perioperative CTx on survival were confirmed in patients with CRS and TBS scores =2 (p = 0.022 and p = 0.020, respectively) and in patients with a GAME score =1 (p = 0.006). CONCLUSION: Perioperative CTx demonstrated an increase in OS in patients with CRLM. Patients with a low-risk of recurrence seem to benefit from systemic treatment.

Published
2021

6. Meta-analysis of vascular endothelial growth factor variations in amyotrophic lateral sclerosis: increased susceptibility in male carriers of the -2578AA genotype

Author

Lambrechts, D., Poesen, K., Fernandez-Santiago, R., Al-Chalabi, A., Del Bo, R., Van Vught, P.W.J., Khan, S., Marklund, S.L., Brockington, A., van Marion, I., Anneser, J., Shaw, C., Ludolph, A.C., Leigh, N. P., Comi, G.P., Gasser, T., Shaw, P.J., Morrison, K.E., Andersen, P.M., Van den, Berg, L.H., Thijs, V., Siddique, T., Robberecht, W., and Carmeliet, P.

Subjects
Vascular endothelial growth factor -- Analysis, Amyotrophic lateral sclerosis -- Research, Amyotrophic lateral sclerosis -- Genetic aspects, Disease susceptibility -- Research, Genotype -- Research, Health
Published
2009

7. Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset

Author

Billingsley, Kimberley J, Barbosa, Ines A, Bandres-Ciga, Sara, Quinn, John P, Bubb, Vivien J, Deshpande, Charu, Botia, Juan A, Reynolds, Regina H, Zhang, David, Simpson, Michael A, Blauwendraat, Cornelis, Gan-Or, Ziv, Gibbs, J Raphael, Nalls, Mike A, Singleton, Andrew, Ryten, Mina, Koks, Sulev, Noyce, A, Tucci, A, Middlehurst, B, Kia, D, Tan, M, Houlden, H, Morris, HR, Plun-Favreau, H, Holmans, P, Hardy, J, Trabzuni, D, Bras, J, Mok, K, Kinghorn, K, Wood, N, Lewis, P, Guerreiro, R, Loverin, R, R'Bibo, L, Rizig, M, Escott-Price, V, Chelban, V, Foltynie, T, Williams, N, Brice, A, Danjou, F, Lesage, S, Martinez, M, Giri, A, Schulte, C, Brockmann, K, Simon-Sanchez, J, Heutink, P, Rizzu, P, Sharma, M, Gasser, T, Nicolas, A, Cookson, M, Faghri, F, Hernandez, D, Shulman, J, Robak, L, Lubbe, S, Finkbeiner, S, Mencacci, N, Lungu, C, Scholz, S, Reed, X, Leonard, H, Rouleau, G, Krohan, L, van Hilten, J, Marinus, J, Adarmes-Gomez, A, Aguilar, M, Alvarez, I, Alvarez, V, Javier Barrero, F, Bergareche Yarza, J, Bernal-Bernal, I, Blazquez, M, Bonilla-Toribio Bernal, M, Boungiorne, M, Buiza-Rueda, Dolores, Camara, A, Carcel, M, Carrillo, F, Carrion-Claro, M, Cerdan, D, Clarimon, J, Compta, Y, Diez-Fairen, M, Dols-Icardo, O, Duarte, J, Duran, RI, Escamilla-Sevilla, F, Ezquerra, M, Fernandez, M, Fernandez-Santiago, R, Garcia, C, Garcia-Ruiz, P, Gomez-Garre, P, Gomez Heredia, M, Gonzalez-Aramburu, I, Gorostidi Pagola, A, Hoenicka, J, Infante, J, Jesus, S, Jimenez-Escrig, A, Kulisevsky, J, Labrador-Espinosa, M, Lopez-Sendon, J, de Munain Arregui, A Lopez, Macias, D, Martinez Torres, I, Marin, J, Jose Marti, M, Martinez-Castrillo, J, Mendez-del-Barrio, C, Menendez Gonzalez, M, Minguez, A, Mir, P, Mondragon Rezola, E, Munoz, E, Pagonabarraga, J, Pastor, P, Perez Errazquin, F, Perinan-Tocino, T, Ruiz-Martinez, J, Ruz, C, Sanchez Rodriguez, A, Sierra, M, Suarez-Sanmartin, E, Tabernero, C, Pablo Tartari, J, Tejera-Parrado, C, Tolosa, E, Valldeoriola, F, Vargas-Gonzalez, L, Vela, L, Vives, F, Zimprich, A, Pihlstrom, L, Taba, P, Majamaa, K, Siitonen, A, Okubadejo, N, Ojo, O, IPDGC, and Universidad de Cantabria

Subjects
0301 basic medicine, Mitochondrial DNA, medicine.medical_specialty, Aging, Parkinson's disease, Mitochondrial disease, Mitochondrion, Biology, Neurodegenerative, Bioinformatics, lcsh:RC346-429, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Mendelian randomization, Mitophagy, medicine, Genetics, 2.1 Biological and endogenous factors, Aetiology, lcsh:Neurology. Diseases of the nervous system, Parkinson's Disease, Medical genetics, Neurosciences, medicine.disease, Brain Disorders, International Parkinson’s Disease Genomics Consortium, 030104 developmental biology, Proteostasis, Neurology, Risk factors, Neurological, Neurology (clinical), Medical genetic, 030217 neurology & neurosurgery
Abstract

Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson’s disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial functionassociated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD., This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project ZO1 AG000949

Published
2019

8. Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability

Author

Reynolds, R.H., Botia, J., Nalls, M.A., Hardy, J., Taliun, S.A.G., Ryten, M., Noyce, A.J., Nicolas, A., Cookson, M.R., Bandres-Ciga, S., Gibbs, J.R., Hernandez, D.G., Singleton, A.B., Reed, X., Leonard, H., Blauwendraat, C., Faghri, F., Bras, J., Guerreiro, R., Tucci, A., Kia, D.A., Houlden, H., Plun-Favreau, H., Mok, K.Y., Wood, N.W., Lovering, R., R'Bibo, L., Rizig, M., Chelban, V., Trabzuni, D., Tan, M., Morris, H.R., Middlehurst, B., Quinn, J., Billingsley, K., Holmans, P., Kinghorn, K.J., Lewis, P., Escott-Price, V., Williams, N., Foltynie, T., Brice, A., Danjou, F., Lesage, S., Corvol, J.C., Martinez, M., Giri, A., Schulte, C., Brockmann, K., Simon-Sanchez, J., Heutink, P., Gasser, T., Rizzu, P., Sharma, M., Shulman, J.M., Robak, L., Lubbe, S., Mencacci, N.E., Finkbeiner, S., Lungu, C., Scholz, S.W., Gan-Or, Z., Rouleau, G.A., Krohan, L., Hilten, J.J. van, Marinus, J., Adarmes-Gomez, A.D., Bernal-Bernal, I., Bonilla-Toribio, M., Buiza-Rueda, D., Carrillo, F., Carrion-Claro, M., Mir, P., Gomez-Garre, P., Jesus, S., Labrador-Espinosa, M.A., Macias, D., Vargas-Gonzalez, L., Mendez-del-Barrio, C., Perinan-Tocino, T., Tejera-Parrado, C., Diez-Fairen, M., Aguilar, M., Alvarez, I., Boungiorno, M.T., Carcel, M., Pastor, P., Tartari, J.P., Alvarez, V., Gonzalez, M.M., Blazquez, M., Garcia, C., Suarez-Sanmartin, E., Barrero, F.J., Rezola, E.M., Yarza, J.A.B., Pagola, A.G., Arregui, A.L.D., Ruiz-Martinez, J., Cerdan, D., Duarte, J., Clarimon, J., Dols-Icardo, O., Infante, J., Marin, J., Kulisevsky, J., Pagonabarraga, J., Gonzalez-Aramburu, I., Rodriguez, A.S., Sierra, M., Duran, R., Ruz, C., Vives, F., Escamilla-Sevilla, F., Minguez, A., Camara, A., Compta, Y., Ezquerra, M., Marti, M.J., Fernandez, M., Munoz, E., Fernandez-Santiago, R., Tolosa, E., Valldeoriola, F., Garcia-Ruiz, P., Heredia, M.J.G., Errazquin, F.P., Hoenicka, J., Jimenez-Escrig, A., Martinez-Castrillo, J.C., Lopez-Sendon, J.L., Torres, I.M., Tabernero, C., Vela, L., Zimprich, A., Pihlstrom, L., Koks, S., Taba, P., Majamaa, K., Siitonen, A., Okubadejo, N.U., Ojo, O.O., Pitcher, T., Anderson, T., Bentley, S., Fowdar, J., Mellick, G., Dalrymple-Alford, J., Henders, A.K., Kassam, I., Montgomery, G., Sidorenko, J., Zhang, F.T., Xue, A.L., Vallerga, C.L., Wallace, L., Wray, N.R., Yang, J., Visscher, P.M., Gratten, J., Silburn, P.A., Halliday, G., Hickie, I., Kwok, J., Lewis, S., Kennedy, M., Pearson, J., Int Parkinsons Dis Genomics, and Syst Genomics Parkinsons Dis

Published
2019

9. SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease

Author

Fernandez-Santiago, R., Martin-Flores, N., Antonelli, F., Cerquera, C., Moreno, V., Bandres-Ciga, S., Manduchi, E., Tolosa, E., Singleton, A.B., Moore, J.H., Noyce, A.J., Kaiyrzhanov, R., Middlehurst, B., Kia, D.A., Tan, M., Houlden, H., Morris, H.R., Plun-Favreau, H., Holmans, P., Hardy, J., Trabzuni, D., Bras, J., Quinn, J., Mok, K.Y., Kinghorn, K.J., Billingsley, K., Wood, N.W., Lewis, P., Schreglmann, S., Guerreiro, R., Lovering, R., R'Bibo, L., Manzoni, C., Rizig, M., Ryten, M., Guelfi, S., Escott-Price, V., Chelban, V., Foltynie, T., Williams, N., Morrison, K.E., Clarke, C., Brice, A., Danjou, F., Lesage, S., Corvol, J.C., Martinez, M., Schulte, C., Brockmann, K., Simoon-Saanchez, J., Heutink, P., Rizzu, P., Sharma, M., Gasser, T., Nicolas, A., Cookson, M.R., Blauwendraat, C., Craig, D.W., Faghri, F., Gibbs, J.R., Hernandez, D.G., Keuren-Jensen, K. van, Shulman, J.M., Iwaki, H., Leonard, H.L., Nalls, M.A., Robak, L., Lubbe, S., Finkbeiner, S., Mencacci, N.E., Lungu, C., Scholz, S.W., Reed, X., Alcalay, R.N., Gan-Or, Z., Rouleau, G.A., Krohn, L., Hilten, J.J. van, Marinus, J., Adarmes-Goomez, A.D., Aguilar, I., Alvarez, I., Alvarez, V., Barrero, F.J., Yarza, J.A.B., Bernal-Bernal, I., Blazquez, M., Bonilla-Toribio, M., Botia, J.A., Boungiorno, M.T., Buiza-Rueda, D., Camara, A., Carrillo, F., Carrion-Claro, M., Cerdan, D., Clarimon, J., Compta, Y., Casa, B. de la, Diez-Fairen, M., Dols-Icardo, O., Duarte, J., Duran, R., Escamilla-Sevilla, F., Ezquerra, M., Feliz, C., Fernandez, M., Garcia, C., Garcia-Ruiz, P., Gomez-Garre, P., Heredia, M.J.G., Gonzalez-Aramburu, I., Pagola, A.G., Hoenicka, J., Infante, J., Jesus, S., Jimenez-Escrig, A., Kulisevsky, J., Labrador-Espinosa, M.A., Lopez-Sendon, J.L., Arregui, A.L.D., Macias, D., Torres, I.M., Marin, J., Marti, M.J., Martinez-Castrillo, C., Mendez-del-Barrio, C., Gonzalez, M.M., Mata, M., Minguez, A., Mir, P., Rezola, E.M., Munoz, E., Pagonabarraga, J., Pascual-Sedano, B., Pastor, P., Errazquin, F.P., Perinan-Tocino, T., Ruiz-Martinez, J., Ruz, C., Rodriguez, A.S., Sierra, M., Suarez-Sanmartin, E., Tabernero, C., Tartari, J.P., Tejera-Parrado, C., Valldeoriola, F., Vargas-Gonzalez, L., Vela, L., Vives, F., Zimprich, A., Pihlstrom, L., Toft, M., Koks, S., Taba, P., Hassin-Baer, S., Malagelada, C., Int Parkinson's Dis Genomics Conso, Fundació La Marató de TV3, Michael J. Fox Foundation for Parkinson's Research, National Institutes of Health (US), Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), and Ministerio de Ciencia, Innovación y Universidades (España)

Subjects
0301 basic medicine, epistasis, Male, Parkinson's disease, very elderly, alpha-synuclein, Alpha‐synuclein, regulatory associated protein of mTOR, Cohort Studies, 0302 clinical medicine, single nucleotide polymorphism, genetics, Age of Onset, Genetics, Aged, 80 and over, Polymorphism, Single Nucleoti, biology, TOR Serine-Threonine Kinases, target of rapamycin kinase, fchsd1 gene, Age at onset, Chromosome Mapping, glycogen synthase kinase 3beta, Parkinson Disease, Middle Aged, cohort analysis, LRRK2, priority journal, Neurology, chromosomal mapping, neuromodulation, mTOR, alpha-Synuclein, Female, age at onset, Signal Transduction, onset age, Adult, MTOR protein, human, protein kinase LKB1, gene locus, Genotype, multifactor dimensionality reduction, SNP, Single-nucleotide polymorphism, rps6ka2 gene, Polymorphism, Single Nucleotide, Risk Assessment, Article, brain function, 03 medical and health sciences, alpha synuclein, medicine, Humans, controlled study, Genetic Predisposition to Disease, human, ddc:610, SNCA protein, human, gene, Mechanistic target of rapamycin, PI3K/AKT/mTOR pathway, mammalian target of rapamycin, Aged, RPTOR, Epistasis, Genetic, Odds ratio, medicine.disease, major clinical study, nervous system diseases, 030104 developmental biology, mTOR signaling, biology.protein, Epistasis, pathology, Neurology (clinical), genetic predisposition, 030217 neurology & neurosurgery
Abstract

Special Issue: Focused Ultrasound in Parkinson's Disease., [Background] Single nucleotide polymorphisms (SNPs) in the α‐synuclein (SNCA ) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine‐rich repeat kinase 2 (LRRK2)‐associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored., [Objectives] The mechanistic target of rapamycin (mTOR ) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO., [Methods] Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium., [Results] In the discovery series cohort, we found a 4‐loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P, [Conclusions] These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. © 2019 International Parkinson and Movement Disorder Society, Funding Information; Fundació la Marató de TV3. Grant Number: 60510; Michael J. Fox Foundation for Parkinson's Research. Grant Numbers: Dyskinesia Challenge 2014, MJF_PPMI_10_001, PI044024; National Institutes of Health. Grant Number: LM010098; Secretaría de Estado de Investigación, Desarrollo e Innovación. Grant Number: SAF2014‐57160R and SAF2017‐88812R.

Published
2019

10. SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease

Author

Martin-Flores, N, Antonelli, F, Cerquera, C, Moreno, V, Manduchi, E, Moore, JH, Noyce, AJ, Kaiyrzhanov, R, Middlehurst, B, Kia, DA, Tan, M, Houlden, H, Morris, HR, Plun-Favreau, H, Holmans, P, Hardy, J, Trabzuni, D, Bras, J, Quinn, J, Mok, KY, Kinghorn, KJ, Billingsley, K, Wood, NW, Lewis, P, Schreglmann, S, Guerreiro, R, Lovering, R, R'Bibo, L, Manzoni, C, Rizig, M, Ryten, M, Guelfi, S, Escott-Price, V, Chelban, V, Foltynie, T, Williams, N, Morrison, KE, Clarke, C, Brice, A, Danjou, F, Lesage, S, Corvol, JC, Martinez, M, Schulte, C, Brockmann, K, Simoon-Saanchez, J, Heutink, P, Rizzu, P, Sharma, M, Gasser, T, Nicolas, A, Cookson, MR, Bandres-Ciga, S, Blauwendraat, C, Craig, DW, Faghri, F, Gibbs, JR, Hernandez, DG, Van Keuren-Jensen, K, Shulman, JM, Iwaki, H, Leonard, HL, Nalls, MA, Robak, L, Lubbe, S, Finkbeiner, S, Mencacci, NE, Lungu, C, Singleton, AB, Scholz, SW, Reed, X, Alcalay, RN, Gan-Or, Z, Rouleau, GA, Krohn, L, van Hilten, JJ, Marinus, J, Adarmes-Goomez, AD, Aguilar, I, Alvarez, I, Alvarez, V, Barrero, FJ, Yarza, JAB, Bernal-Bernal, I, Blazquez, M, Bonilla-Toribio, M, Botia, JA, Boungiorno, MT, Buiza-Rueda, D, Camara, A, Carrillo, F, Carrion-Claro, M, Cerdan, D, Clarimon, J, Compta, Y, de la Casa, B, Diez-Fairen, M, Dols-Icardo, O, Duarte, J, Duran, R, Escamilla-Sevilla, F, Feliz, C, Fernandez, M, Fernandez-Santiago, R, Garcia, C, Garcia-Ruiz, P, Gomez-Garre, P, Heredia, MJG, Gonzalez-Aramburu, I, Pagola, AG, Hoenicka, J, Infante, J, Jesus, S, Jimenez-Escrig, A, Kulisevsky, J, Labrador-Espinosa, MA, Lopez-Sendon, JL, Arregui, ALD, Macias, D, Torres, IM, Marin, J, Marti, MJ, Martinez-Castrillo, C, Mendez-del-Barrio, C, Gonzalez, MM, Mata, M, Minguez, A, Mir, P, Rezola, EM, Munoz, E, Pagonabarraga, J, Pascual-Sedano, B, Pastor, P, Errazquin, FP, Perinan-Tocino, T, Ruiz-Martinez, J, Ruz, C, Rodriguez, AS, Sierra, M, Suarez-Sanmartin, E, Tabernero, C, Tartari, JP, Tejera-Parrado, C, Tolosa, E, Valldeoriola, F, Vargas-Gonzalez, L, Vela, L, Vives, F, Zimprich, A, Pihlstrom, L, Toft, M, Koks, S, Taba, P, Hassin-Baer, S, Ezquerra, M, Malagelada, C, and Int Parkinson's Dis Genomics Conso

Subjects
epistasis, alpha-synuclein, Parkinson's disease, mTOR, SNP, age at onset
Abstract

Background Single nucleotide polymorphisms (SNPs) in the alpha-synuclein (SNCA) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored. Objectives The mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO. Methods Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium. Results In the discovery series cohort, we found a 4-loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P < .001). In addition, we also found a 3-loci epistatic combination of RPTOR rs11868112 and RPS6KA2 rs6456121 with SNCA rs356219, which was associated (odds ratio = 2.89; P < .0001) with differential AAO. The latter was further validated (odds ratio = 1.56; P = 0.046-0.047) in the International Parkinson's Disease Genomics Consortium cohort. Conclusions These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. (c) 2019 International Parkinson and Movement Disorder Society

Published
2019

11. Moving beyond neurons:the role of cell type-specific gene regulation in Parkinson’s disease heritability

Author

Reynolds, R. H. (Regina H.), Botia, J. (Juan), Nalls, M. A. (Mike A.), Hardy, J. (John), Taliun, S. A. (Sarah A. Gagliano), Ryten, M. (Mina), Noyce, A. J. (Alastair J.), Nicolas, A. (Aude), Cookson, M. R. (Mark R.), Bandres-Ciga, S. (Sara), Gibbs, J. R. (J. Raphael), Hernandez, D. G. (Dena G.), Singleton, A. B. (Andrew B.), Reed, X. (Xylena), Leonard, H. (Hampton), Blauwendraat, C. (Cornelis), Faghri, F. (Faraz), Bras, J. (Jose), Guerreiro, R. (Rita), Tucci, A. (Arianna), Kia, D. A. (Demis A.), Houlden, H. (Henry), Plun-Favreau, H. (Helene), Mok, K. Y. (Kin Y.), Wood, N. W. (Nicholas W.), Lovering, R. (Ruth), R'Bibo, L. (Lea), Rizig, M. (Mie), Chelban, V. (Viorica), Trabzuni, D. (Daniah), Tan, M. (Manuela), Morris, H. R. (Huw R.), Middlehurst, B. (Ben), Quinn, J. (John), Billingsley, K. (Kimberley), Holmans, P. (Peter), Kinghorn, K. J. (Kerri J.), Lewis, P. (Patrick), Escott-Price, V. (Valentina), Williams, N. (Nigel), Foltynie, T. (Thomas), Brice, A. (Alexis), Danjou, F. (Fabrice), Lesage, S. (Suzanne), Corvol, J.-C. (Jean-Christophe), Martinez, M. (Maria), Giri, A. (Anamika), Schulte, C. (Claudia), Brockmann, K. (Kathrin), Simon-Sanchez, J. (Javier), Heutink, P. (Peter), Gasser, T. (Thomas), Rizzu, P. (Patrizia), Sharma, M. (Manu), Shulman, J. M. (Joshua M.), Robak, L. (Laurie), Lubbe, S. (Steven), Mencacci, N. E. (Niccolo E.), Finkbeiner, S. (Steven), Lungu, C. (Codrin), Scholz, S. W. (Sonja W.), Gan-Or, Z. (Ziv), Rouleau, G. A. (Guy A.), Krohan, L. (Lynne), van Hilten, J. J. (Jacobus J.), Marinus, J. (Johan), Adarmes-Gomez, A. D. (Astrid D.), Bernal-Bernal, I. (Inmaculada), Bonilla-Toribio, M. (Marta), Buiza-Rueda, D. (Dolores), Carrillo, F. (Fatima), Carrion-Claro, M. (Mario), Mir, P. (Pablo), Gomez-Garre, P. (Pilar), Jesus, S. (Silvia), Labrador-Espinosa, M. A. (Miguel A.), Macias, D. (Daniel), Vargas-Gonzalez, L. (Laura), Mendez-del-Barrio, C. (Carlota), Perinan-Tocino, T. (Teresa), Tejera-Parrado, C. (Cristina), Diez-Fairen, M. (Monica), Aguilar, M. (Miquel), Alvarez, I. (Ignacio), Teresa Boungiorno, M. (Mara), Carcel, M. (Maria), Pastor, P. (Pau), Pablo Tartari, J. (Juan), Alvarez, V. (Victoria), Menendez Gonzalez, M. (Manuel), Blazquez, M. (Marta), Garcia, C. (Ciara), Suarez-Sanmartin, E. (Esther), Javier Barrero, F. (Francisco), Mondragon Rezola, E. (Elisabet), Bergareche Yarza, J. A. (Jesus Alberto), Gorostidi Pagola, A. (Ana), de Munain Arregui, A. L. (Adolfo Lopez), Ruiz-Martinez, J. (Javier), Cerdan, D. (Debora), Duarte, J. (Jacinto), Clarimon, J. (Jordi), Dols-Icardo, O. (Oriol), Infante, J. (Jon), Marin, J. (Juan), Kulisevsky, J. (Jaime), Pagonabarraga, J. (Javier), Gonzalez-Aramburu, I. (Isabel), Sanchez Rodriguez, A. (Antonio), Sierra, M. (Mara), Duran, R. (Raquel), Ruz, C. (Clara), Vives, F. (Francisco), Escamilla-Sevilla, F. (Francisco), Minguez, A. (Adolfo), Camara, A. (Ana), Compta, Y. (Yaroslau), Ezquerra, M. (Mario), Jose Marti, M. (Maria), Fernandez, M. (Manel), Munoz, E. (Esteban), Fernandez-Santiago, R. (Ruben), Tolosa, E. (Eduard), Valldeoriola, F. (Francesc), Garcia-Ruiz, P. (Pedro), Gomez Heredia, M. J. (Maria Jose), Perez Errazquin, F. (Francisco), Hoenicka, J. (Janet), Jimenez-Escrig, A. (Adriano), Carlos Martinez-Castrillo, J. (Juan), Luis Lopez-Sendon, J. (Jose), Martinez Torres, I. (Irene), Tabernero, C. (Cesar), Vela, L. (Lydia), Zimprich, A. (Alexander), Pihlstrom, L. (Lasse), Koks, S. (Sulev), Taba, P. (Pille), Majamaa, K. (Kari), Siitonen, A. (Ari), Okubadejo, N. U. (Njideka U.), Ojo, O. O. (Oluwadamilola O.), Pitcher, T. (Toni), Anderson, T. (Tim), Bentley, S. (Steven), Fowdar, J. (Javed), Mellick, G. (George), Dalrymple-Alford, J. (John), Henders, A. K. (Anjali K.), Kassam, I. (Irfahan), Montgomery, G. (Grant), Sidorenko, J. (Julia), Zhang, F. (Futao), Xue, A. (Angli), Vallerga, C. L. (Costanza L.), Wallace, L. (Leanne), Wray, N. R. (Naomi R.), Yang, J. (Jian), Visscher, P. M. (Peter M.), Gratten, J. (Jacob), Silburn, P. A. (Peter A.), Halliday, G. (Glenda), Hickie, I. (Ian), Kwok, J. (John), Lewis, S. (Simon), Kennedy, M. (Martin), Pearson, J. (John), Reynolds, R. H. (Regina H.), Botia, J. (Juan), Nalls, M. A. (Mike A.), Hardy, J. (John), Taliun, S. A. (Sarah A. Gagliano), Ryten, M. (Mina), Noyce, A. J. (Alastair J.), Nicolas, A. (Aude), Cookson, M. R. (Mark R.), Bandres-Ciga, S. (Sara), Gibbs, J. R. (J. Raphael), Hernandez, D. G. (Dena G.), Singleton, A. B. (Andrew B.), Reed, X. (Xylena), Leonard, H. (Hampton), Blauwendraat, C. (Cornelis), Faghri, F. (Faraz), Bras, J. (Jose), Guerreiro, R. (Rita), Tucci, A. (Arianna), Kia, D. A. (Demis A.), Houlden, H. (Henry), Plun-Favreau, H. (Helene), Mok, K. Y. (Kin Y.), Wood, N. W. (Nicholas W.), Lovering, R. (Ruth), R'Bibo, L. (Lea), Rizig, M. (Mie), Chelban, V. (Viorica), Trabzuni, D. (Daniah), Tan, M. (Manuela), Morris, H. R. (Huw R.), Middlehurst, B. (Ben), Quinn, J. (John), Billingsley, K. (Kimberley), Holmans, P. (Peter), Kinghorn, K. J. (Kerri J.), Lewis, P. (Patrick), Escott-Price, V. (Valentina), Williams, N. (Nigel), Foltynie, T. (Thomas), Brice, A. (Alexis), Danjou, F. (Fabrice), Lesage, S. (Suzanne), Corvol, J.-C. (Jean-Christophe), Martinez, M. (Maria), Giri, A. (Anamika), Schulte, C. (Claudia), Brockmann, K. (Kathrin), Simon-Sanchez, J. (Javier), Heutink, P. (Peter), Gasser, T. (Thomas), Rizzu, P. (Patrizia), Sharma, M. (Manu), Shulman, J. M. (Joshua M.), Robak, L. (Laurie), Lubbe, S. (Steven), Mencacci, N. E. (Niccolo E.), Finkbeiner, S. (Steven), Lungu, C. (Codrin), Scholz, S. W. (Sonja W.), Gan-Or, Z. (Ziv), Rouleau, G. A. (Guy A.), Krohan, L. (Lynne), van Hilten, J. J. (Jacobus J.), Marinus, J. (Johan), Adarmes-Gomez, A. D. (Astrid D.), Bernal-Bernal, I. (Inmaculada), Bonilla-Toribio, M. (Marta), Buiza-Rueda, D. (Dolores), Carrillo, F. (Fatima), Carrion-Claro, M. (Mario), Mir, P. (Pablo), Gomez-Garre, P. (Pilar), Jesus, S. (Silvia), Labrador-Espinosa, M. A. (Miguel A.), Macias, D. (Daniel), Vargas-Gonzalez, L. (Laura), Mendez-del-Barrio, C. (Carlota), Perinan-Tocino, T. (Teresa), Tejera-Parrado, C. (Cristina), Diez-Fairen, M. (Monica), Aguilar, M. (Miquel), Alvarez, I. (Ignacio), Teresa Boungiorno, M. (Mara), Carcel, M. (Maria), Pastor, P. (Pau), Pablo Tartari, J. (Juan), Alvarez, V. (Victoria), Menendez Gonzalez, M. (Manuel), Blazquez, M. (Marta), Garcia, C. (Ciara), Suarez-Sanmartin, E. (Esther), Javier Barrero, F. (Francisco), Mondragon Rezola, E. (Elisabet), Bergareche Yarza, J. A. (Jesus Alberto), Gorostidi Pagola, A. (Ana), de Munain Arregui, A. L. (Adolfo Lopez), Ruiz-Martinez, J. (Javier), Cerdan, D. (Debora), Duarte, J. (Jacinto), Clarimon, J. (Jordi), Dols-Icardo, O. (Oriol), Infante, J. (Jon), Marin, J. (Juan), Kulisevsky, J. (Jaime), Pagonabarraga, J. (Javier), Gonzalez-Aramburu, I. (Isabel), Sanchez Rodriguez, A. (Antonio), Sierra, M. (Mara), Duran, R. (Raquel), Ruz, C. (Clara), Vives, F. (Francisco), Escamilla-Sevilla, F. (Francisco), Minguez, A. (Adolfo), Camara, A. (Ana), Compta, Y. (Yaroslau), Ezquerra, M. (Mario), Jose Marti, M. (Maria), Fernandez, M. (Manel), Munoz, E. (Esteban), Fernandez-Santiago, R. (Ruben), Tolosa, E. (Eduard), Valldeoriola, F. (Francesc), Garcia-Ruiz, P. (Pedro), Gomez Heredia, M. J. (Maria Jose), Perez Errazquin, F. (Francisco), Hoenicka, J. (Janet), Jimenez-Escrig, A. (Adriano), Carlos Martinez-Castrillo, J. (Juan), Luis Lopez-Sendon, J. (Jose), Martinez Torres, I. (Irene), Tabernero, C. (Cesar), Vela, L. (Lydia), Zimprich, A. (Alexander), Pihlstrom, L. (Lasse), Koks, S. (Sulev), Taba, P. (Pille), Majamaa, K. (Kari), Siitonen, A. (Ari), Okubadejo, N. U. (Njideka U.), Ojo, O. O. (Oluwadamilola O.), Pitcher, T. (Toni), Anderson, T. (Tim), Bentley, S. (Steven), Fowdar, J. (Javed), Mellick, G. (George), Dalrymple-Alford, J. (John), Henders, A. K. (Anjali K.), Kassam, I. (Irfahan), Montgomery, G. (Grant), Sidorenko, J. (Julia), Zhang, F. (Futao), Xue, A. (Angli), Vallerga, C. L. (Costanza L.), Wallace, L. (Leanne), Wray, N. R. (Naomi R.), Yang, J. (Jian), Visscher, P. M. (Peter M.), Gratten, J. (Jacob), Silburn, P. A. (Peter A.), Halliday, G. (Glenda), Hickie, I. (Ian), Kwok, J. (John), Lewis, S. (Simon), Kennedy, M. (Martin), and Pearson, J. (John)

Abstract

Parkinson’s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types.

Published
2019

13. Liver resection in elderly with extended CRLM, is surgery still justified? A propensity score matched analysis

Author

Di Martino, M., Dorcaratto, D., Blanco Terés, L., Primavesi, F., Syn, N., Dupré, A., Piardi, T., Rami, R., Blanco Fernández, G., Prada Villaverde, A., Rodríguez Sanjuán, J.C., Fernández Santiago, R., Fernández-Moreno, M., Ferret, G., López Ben, S., Suárez Muñoz, M.Á., Perez-Alonso, A.J., Koh, Y.-X., Jones, R., and Martín-Pérez, E.

Published
2021
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14. Neoadjuvant versus Perioperative Chemotherapy for Resectable Colorectal Liver Metastases: An International Multicentre Propensity-score Matched Analysis

Author

Di Martino, M., Primavesi, F., De la Hoz Rodríguez, Á., Dorcaratto, D., Syn, N., Dupré, A., Piardi, T., Rami, R., Blanco Fernández, G., De-Armas-Conde, N., Rodríguez Sanjuán, J.C., Fernández Santiago, R., Fernández-Moreno, M., Ferret, G., López Ben, S., Suárez Muñoz, M.Á., Perez-Alonso, A.J., Koh, Y.-X., Jones, R., and Martín-Pérez, E.

Published
2021
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19. NeuroChip, an updated version of the NeuroX genotyping platform to rapidly screen for variants associated with neurological diseases

Author

Blauwendraat, C., Faghri, F., Pihlstrom, L., Geiger, J. T., Elbaz, A., Lesage, S., Corvol, J. -C., May, P., Nicolas, A., Abramzon, Y., Murphy, N. A., Gibbs, J. R., Ryten, M., Ferrari, R., Bras, J., Guerreiro, R., Williams, J., Sims, R., Lubbe, S., Hernandez, D. G., Mok, K. Y., Robak, L., Campbell, R. H., Rogaeva, E., Traynor, B. J., Chia, R., Chung, S. J., Hardy, J. A., Brice, A., Wood, N. W., Houlden, H., Shulman, J. M., Morris, H. R., Gasser, T., Kruger, R., Heutink, P., Sharma, M., Simon-Sanchez, J., Nalls, M. A., Singleton, A. B., Scholz, S. W., Noyce, A. J., Giri, A., Oehmig, A., Tucci, A., Schulte, C., Cookson, M. R., Kia, D., Danjou, F., Charlesworth, G., Plun-Favreau, H., Holmans, P., Jansen, I., Hardy, J., Bras, J. M., Quinn, J., Botia, J. A., Billingsley, K., R'Bibo, L., Lungu, C., Martinez, M., Escott-Price, V., Mencacci, N. E., Topley, Lewis, Denny, P., Rizzu, P., Taba, P., Lovering, R., Ogalla, R. D., Foulger, R., Finkbeiner, S., Sveinbjornsdottir, S., Scholz, S., Koks, S., Foltynie, T., Price, T. R., Sheerin, U. -M., Williams, N., Reed, X., Wang, L., Brockmann, K., Oertel, W., Klein, C., Mohamed, F., Malard, L., Corti, O., Drouet, V., Goldwurm, S., Tesei, S., Canesi, M., Valente, E. M., Petrucci, S., Ginevrino, M., Toft, M., Aasly, J., Henriksen, S. P., Saetehaug, C., Orr-Urtreger, A., Giladi, N., Ferreira, J., Guedes, L. C., Bouca-Machado, R., Coelho, M., Rosa, M. M., Tolosa, E., Fernandez-Santiago, R., Ezquerra, M., Marti, M. J., Glaab, E., Balling, R., and Chung, S. -J.

Subjects
0301 basic medicine, Aging, methods [Genome-Wide Association Study], 0302 clinical medicine, Corticobasal degeneration, neurodegenerative diseases, humans, risk, high-throughput screening assays, education.field_of_study, General Neuroscience, neurodegeneration, genetics [Genetic Variation], 3. Good health, Neurochip, alleles, methods [Genotyping Techniques], Frontotemporal dementia, Risk, Population, methods [High-Throughput Screening Assays], Computational biology, Genetic screening, genotyping, NeuroChip, NeuroX, apolipoproteins E, genetic variation, genome-wide association study, genotyping techniques, Article, Progressive supranuclear palsy, 03 medical and health sciences, Apolipoproteins E, medicine, Humans, Dementia, ddc:610, education, Genotyping, Alleles, business.industry, medicine.disease, 030104 developmental biology, genetics [Neurodegenerative Diseases], genetics [Apolipoproteins E], Neurology (clinical), Geriatrics and Gerontology, business, Neuroscience, 030217 neurology & neurosurgery, Imputation (genetics), Developmental Biology
Abstract

Genetics has proven to be a powerful approach in neurodegenerative diseases research, resulting in the identification of numerous causal and risk variants. Previously, we introduced the NeuroX Illumina genotyping array, a fast and efficient genotyping platform designed for the investigation of genetic variation in neurodegenerative diseases. Here, we present its updated version, named NeuroChip. The NeuroChip is a low-cost, custom-designed array containing a tagging variant backbone of about 306,670 variants complemented with a manually curated custom content comprised of 179,467 variants implicated in diverse neurological diseases, including Alzheimer's disease, Parkinson's disease, Lewy body dementia, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy. The tagging backbone was chosen because of the low cost and good genome-wide resolution; the custom content can be combined with other backbones, like population or drug development arrays. Using the NeuroChip, we can accurately identify rare variants and impute over 5.3 million common SNPs from the latest release of the Haplotype Reference Consortium. In summary, we describe the design and usage of the NeuroChip array and show its capability for detecting rare pathogenic variants in numerous neurodegenerative diseases. The NeuroChip has a more comprehensive and improved content, which makes it a reliable, high-throughput, cost-effective screening tool for genetic research and molecular diagnostics in neurodegenerative diseases.

Published
2017

20. Fused in Sarcoma (FUS) gene mutations are not a frequent cause of essential tremor in Europeans

Author

Ortega-Cubero, S, Lorenzo-Betancor, O, Lorenzo, E, Alonso, E, Coria, F, Pastor, MA, Fernandez-Santiago, R, Marti, MJ, Ezquerra, M, Valldeoriola, F, Compta, Y, Tolosa, E, Agundez, JA, Jimenez-Jimenez, FJ, Gironell, A, Clarimon, J, de Castro, P, Garcia-Martin, E, Alonso-Navarro, H, and Pastor, P

Subjects
Essential tremor, Sequencing, FUS
Abstract

FUS/TLS (denoting fused in sarcoma/translocated in liposarcoma [MIM 137070]) codifies an RNA binding protein. Mutations in this gene cause amyotrophic lateral sclerosis (ALS; MIM 608030). Essential tremor (ET [MIM 190300]) is the most frequent movement disorder. Despite its strong familiar aggregation, recently a whole exome sequencing study has identified FUS mutations as a cause of familial ET. To determine whether mutations in FUS are also common in other populations, we sequenced FUS gene in 178 unrelated Spanish subjects with ET. We detected only an intronic single-pair nucleotide deletion (c.1293-37delC), which was predicted to affect mRNA splicing. However, leukocyte mRNA analysis showed no changes in FUS expression. In conclusion, coding or splicing FUS mutations are not a frequent cause of ET in the Spanish population. (c) 2013 Elsevier Inc. All rights reserved.

Published
2013

22. Mutant superoxide dismutase-1 indistinguishable from wild-type causes ALS

Author

Synofzik, M., Ronchi, D., Keskin, I., Basak, A.N., Wilhelm, C., Gobbi, C., Birve, A., Biskup, S., Zecca, C., Fernandez-Santiago, R., Kaugesaar, Toomas, Schols, L., Marklund, S.L., Andersen, P.M., Synofzik, M., Ronchi, D., Keskin, I., Basak, A.N., Wilhelm, C., Gobbi, C., Birve, A., Biskup, S., Zecca, C., Fernandez-Santiago, R., Kaugesaar, Toomas, Schols, L., Marklund, S.L., and Andersen, P.M.

Abstract

A reason for screening amyotrophic lateral sclerosis (ALS) patients for mutations in the superoxide dismutase-1 (SOD1) gene is the opportunity to find novel mutations with properties that can give information on pathogenesis. A novel c.352Cgreater thanG (L117V) SOD1 mutation was found in two Syrian ALS families living in Europe. The disease showed unusually low penetrance and slow progression. In erythrocytes, the total SOD1 activity, as well as specific activity of the mutant protein, was equal in carriers of the mutation and family controls lacking SOD1 mutations. The structural stabilities of the L117V mutant and wild-type SOD1 under denaturing conditions were likewise equal, but considerably lower than that of murine SOD1. As analyzed with an ELISA specific for misfolded SOD1 species, no differences were found in the content of misfolded SOD1 protein between extracts of fibroblasts from wild-type controls and from an L117V patient. In contrast, elevated levels of misfolded SOD1 protein were found in fibroblasts from ALS patients carrying seven other mutations in the SOD1 gene. We conclude that mutations in SOD1 that result in a fully stable protein are associated with low disease penetrance for ALS and may be found in cases of apparently sporadic ALS. Wild-type human SOD1 is moderately stable, and was found here to be within the stability range of ALS-causing SOD1 variants, lending support to the hypothesis that wild-type SOD1 could be more generally involved in ALS pathogenesis.

Published
2012
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23. Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis.

Author

Es, M.A. van, Schelhaas, H.J., Vught, P.W. van, Ticozzi, N., Andersen, P.M., Groen, E.J., Schulte, C., Blauw, H.M., Koppers, M., Diekstra, F.P., Fumoto, K., Leclerc, A.L., Keagle, P., Bloem, B.R., Scheffer, H., Nuenen, B.F.L. van, Blitterswijk, M. van, Rheenen, W. van, Wills, A.M., Lowe, P.P., Hu, G.F., Yu, W., Kishikawa, H., Wu, D., Folkerth, R.D., Mariani, C., Goldwurm, S., Pezzoli, G., Damme, P. van, Lemmens, R., Dahlberg, C., Birve, A., Fernandez-Santiago, R., Waibel, S., Klein, C., Weber, M., Kooi, A.J. van der, Visser, M. de, Verbaan, D., Hilten, J.J. van, Heutink, P., Hennekam, E.A., Cuppen, E., Berg, D., Brown, R.H. Jr., Silani, V., Gasser, T., Ludolph, A.C., Robberecht, W., Ophoff, R.A., Veldink, J.H., Pasterkamp, R.J., Bakker, P.I. de, Landers, J.E., Warrenburg, B.P.C. van de, Berg, L.H. van den, Es, M.A. van, Schelhaas, H.J., Vught, P.W. van, Ticozzi, N., Andersen, P.M., Groen, E.J., Schulte, C., Blauw, H.M., Koppers, M., Diekstra, F.P., Fumoto, K., Leclerc, A.L., Keagle, P., Bloem, B.R., Scheffer, H., Nuenen, B.F.L. van, Blitterswijk, M. van, Rheenen, W. van, Wills, A.M., Lowe, P.P., Hu, G.F., Yu, W., Kishikawa, H., Wu, D., Folkerth, R.D., Mariani, C., Goldwurm, S., Pezzoli, G., Damme, P. van, Lemmens, R., Dahlberg, C., Birve, A., Fernandez-Santiago, R., Waibel, S., Klein, C., Weber, M., Kooi, A.J. van der, Visser, M. de, Verbaan, D., Hilten, J.J. van, Heutink, P., Hennekam, E.A., Cuppen, E., Berg, D., Brown, R.H. Jr., Silani, V., Gasser, T., Ludolph, A.C., Robberecht, W., Ophoff, R.A., Veldink, J.H., Pasterkamp, R.J., Bakker, P.I. de, Landers, J.E., Warrenburg, B.P.C. van de, and Berg, L.H. van den

Abstract

1 december 2011, Contains fulltext : 95644.pdf (publisher's version ) (Closed access), OBJECTIVE: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD. METHODS: We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios. RESULTS: Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 x 10(-6) for ALS and p = 4.3 x 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD. INTERPRETATION: The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD. ANN NEUROL 2011;70:964-973.

Published
2011

24. Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis

Author

van Es, M.A., Schelhaas, H.J., van Vught, P.W., Ticozzi, N., Andersen, P.M., Groen, E.J., Schulte, C., Blauw, H.M., Koppers, M., Diekstra, F.P., Fumoto, K., Leclerc, A.L., Keagle, P., Bloem, B.R., Scheffer, H., van Nuenen, B.F., van Blitterswijk, M., van Rheenen, W., Wills, A.M., Lowe, P.P., Hu, G.F., Yu, W., Kishikawa, H., Wu, D., Folkerth, R.D., Mariani, C., Goldwurm, S., Pezzoli, G., van Damme, P.A., Lemmens, R., Dahlberg, C., Birve, A., Fernandez-Santiago, R., Waibel, S., Klein, C., Weber, M., van der Kooi, A.J., de Visser, M., Verbaan, D., van Hilten, J.J., Heutink, P., Hennekam, E.A., Cuppen, E., Berg, D., Brown Jr., R.H., Silani, V., Gasser, T., Ludolph, A.C., Robberecht, W., Ophoff, R.A., Veldink, J.H., Pasterkamp, R.J., Bakker, P.A.H.M., Landers, J.E., van de Warrenburg, B.P., van den Berg, L., van Es, M.A., Schelhaas, H.J., van Vught, P.W., Ticozzi, N., Andersen, P.M., Groen, E.J., Schulte, C., Blauw, H.M., Koppers, M., Diekstra, F.P., Fumoto, K., Leclerc, A.L., Keagle, P., Bloem, B.R., Scheffer, H., van Nuenen, B.F., van Blitterswijk, M., van Rheenen, W., Wills, A.M., Lowe, P.P., Hu, G.F., Yu, W., Kishikawa, H., Wu, D., Folkerth, R.D., Mariani, C., Goldwurm, S., Pezzoli, G., van Damme, P.A., Lemmens, R., Dahlberg, C., Birve, A., Fernandez-Santiago, R., Waibel, S., Klein, C., Weber, M., van der Kooi, A.J., de Visser, M., Verbaan, D., van Hilten, J.J., Heutink, P., Hennekam, E.A., Cuppen, E., Berg, D., Brown Jr., R.H., Silani, V., Gasser, T., Ludolph, A.C., Robberecht, W., Ophoff, R.A., Veldink, J.H., Pasterkamp, R.J., Bakker, P.A.H.M., Landers, J.E., van de Warrenburg, B.P., and van den Berg, L.

Abstract

OBJECTIVE: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD. METHODS: We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios. RESULTS: Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 x 10(-6) for ALS and p = 4.3 x 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD. INTERPRETATION: The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD. ANN NEUROL 2011;70:964-973., OBJECTIVE: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD. METHODS: We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios. RESULTS: Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 x 10(-6) for ALS and p = 4.3 x 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD. INTERPRETATION: The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD. ANN NEUROL 2011;70:964-973.

Published
2011

27. Meta-analysis of vascular endothelial growth factor variations in amyotrophic lateral sclerosis: increased susceptibility in male carriers of the -2578AA genotype

Author

Lambrechts, D, primary, Poesen, K, additional, Fernandez-Santiago, R, additional, Al-Chalabi, A, additional, Del Bo, R, additional, Van Vught, P W J, additional, Khan, S, additional, Marklund, S L, additional, Brockington, A, additional, van Marion, I, additional, Anneser, J, additional, Shaw, C, additional, Ludolph, A C, additional, Leigh, N P, additional, Comi, G P, additional, Gasser, T, additional, Shaw, P J, additional, Morrison, K E, additional, Andersen, P M, additional, Van den Berg, L H, additional, Thijs, V, additional, Siddique, T, additional, Robberecht, W, additional, and Carmeliet, P, additional

Published
2008
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30. Transcriptomic differences in MSA clinical variants

Author

Perez-Soriano, A., Arnal Segura, M., Botta-Orfila, T., Giraldo, D., Fernandez, M., Compta, Y., Fernandez-Santiago, R., Ezquerra, M., Tartaglia, G. G., Marti, M. J., Munoz, E., Pagonabarraga, J., Valldeoriola, F., Hernandez-Vara, J., Classen, S. J., Puente, V., Pont, C., Caballol, N., de Fabregues, O., Avila, A., Calopa, M., Gaig, C., Pastor, P., Pujol, M., Santamaria, J., Planellas, L., and Camara, A.

Subjects
Male, Multiple system atrophy (MSA), Parkinson's disease, lcsh:Medicine, Disease, Transcriptome, 0302 clinical medicine, Malaltia de Parkinson, Cerebellum, Gene expression, lcsh:Science, Genetics, 0303 health sciences, Multidisciplinary, Parkinsonism, Cerebel, Parkinson Disease, Middle Aged, Phenotype, parkinsonism (MSA-P), 3. Good health, Neurology, Differential diagnosis, Female, Biology, cerebellar dysfunction (MSA-C), Article, Diagnosis, Differential, 03 medical and health sciences, Atrophy, stomatognathic system, Cerebellar Diseases, parasitic diseases, mental disorders, medicine, Humans, Movement disorders, Gene, 030304 developmental biology, Aged, Synucleinopathies, Gene Expression Profiling, lcsh:R, Diagnòstic diferencial, Multiple System Atrophy, medicine.disease, Expressió gènica, nervous system diseases, Computational biology and bioinformatics, nervous system, Case-Control Studies, lcsh:Q, 030217 neurology & neurosurgery, Neurological disorders, Neuroscience
Abstract

Background: Multiple system atrophy (MSA) is a rare oligodendroglial synucleinopathy of unknown etiopathogenesis including two major clinical variants with predominant parkinsonism (MSA-P) or cerebellar dysfunction (MSA-C). Objective: To identify novel disease mechanisms we performed a blood transcriptomic study investigating differential gene expression changes and biological process alterations in MSA and its clinical subtypes. Methods: We compared the transcriptome from rigorously gender and age-balanced groups of 10 probable MSA-P, 10 probable MSA-C cases, 10 controls from the Catalan MSA Registry (CMSAR), and 10 Parkinson Disease (PD) patients. Results: Gene set enrichment analyses showed prominent positive enrichment in processes related to immunity and inflammation in all groups, and a negative enrichment in cell differentiation and development of the nervous system in both MSA-P and PD, in contrast to protein translation and processing in MSA-C. Gene set enrichment analysis using expression patterns in different brain regions as a reference also showed distinct results between the different synucleinopathies. Conclusions: In line with the two major phenotypes described in the clinic, our data suggest that gene expression and biological processes might be differentially affected in MSA-P and MSA-C. Future studies using larger sample sizes are warranted to confirm these results. We would like to thank all the patients for their always willing and generous collaboration. This project has been possible thanks to the funding from the Fundació Marató TV3 and CERCA Programme from Generalitat de Catalunya. We also thank the European Research Council RIBOMYLOME_309545 and Spanish Ministry of Economy and Competitiveness (BFU2017-86970-P). A.P.-S. was funded by a PHD4MD grant, which is a collaborative research training program for medical doctors. R.F.-S. was supported by a Jóvenes Investigadores (JIN) grant of the Spanish Ministry of Economy and Competitiveness (MINECO) and the Agencia Estatal de Investigación (AEI) (AEI/FEDER/UE) (grant # SAF2015-73508-JIN), and a Miguel Servet grant from the Instituto de Salud Carlos III (grant # CP19/00048). M.F. was funded by María de Maeztu programme (grant # MDM-2017-0729). Thanks to Lara Nonell, head of the Human Computational Biology group in IMIM, for offering the computational resources in the institution and the help with data management.

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31. Cumulative Genetic Score and C9orf72 Repeat Status Independently Contribute to Amyotrophic Lateral Sclerosis Risk in 2 Case-Control Studies.

Author

Dou J, Bakulski K, Guo K, Hur J, Zhao L, Saez-Atienzar S, Stark A, Chia R, García-Redondo A, Rojas-Garcia R, Vázquez Costa JF, Fernandez Santiago R, Bandres-Ciga S, Gómez-Garre P, Periñán MT, Mir P, Pérez-Tur J, Cardona F, Menendez-Gonzalez M, Riancho J, Borrego-Hernández D, Galán-Dávila L, Infante Ceberio J, Pastor P, Paradas C, Dols-Icardo O, Traynor BJ, Feldman EL, and Goutman SA

Abstract

Background and Objectives: Most patients with amyotrophic lateral sclerosis (ALS) lack a monogenic mutation. This study evaluates ALS cumulative genetic risk in an independent Michigan and Spanish replication cohort using polygenic scores., Methods: Participant samples from University of Michigan were genotyped and assayed for the chromosome 9 open reading frame 72 hexanucleotide expansion. Final cohort size was 219 ALS and 223 healthy controls after genotyping and participant filtering. Polygenic scores excluding the C9 region were generated using an independent ALS genome-wide association study (20,806 cases, 59,804 controls). Adjusted logistic regression and receiver operating characteristic curves evaluated the association and classification between polygenic scores and ALS status, respectively. Population attributable fractions and pathway analyses were conducted. An independent Spanish study sample (548 cases, 2,756 controls) was used for replication., Results: Polygenic scores constructed from 275 single-nucleotide variation (SNV) had the best model fit in the Michigan cohort. An SD increase in ALS polygenic score associated with 1.28 (95% CI 1.04-1.57) times higher odds of ALS with area under the curve of 0.663 vs a model without the ALS polygenic score ( p value = 1 × 10 -6 ). The population attributable fraction of the highest 20th percentile of ALS polygenic scores, relative to the lowest 80th percentile, was 4.1% of ALS cases. Genes annotated to this polygenic score enriched for important ALS pathomechanisms. Meta-analysis with the Spanish study, using a harmonized 132 single nucleotide variation polygenic score, yielded similar logistic regression findings (odds ratio: 1.13, 95% CI 1.04-1.23)., Discussion: ALS polygenic scores can account for cumulative genetic risk in populations and reflect disease-relevant pathways. If further validated, this polygenic score will inform future ALS risk models., Competing Interests: J.F. Vázquez-Costa receives payment for lectures and presentations from Biogen. P. Mir receives payments for honoraria or lectures from Abbvie, Abbott, and Zambon. L. Galán-Dávila receives consulting fees, payment, or honoraria from Akcea, Alnylan, Genzyme, Sobi, Pfizer, and equipment donation from Pfizer. J.I. Ceberio receives payment for lectures and presentations from Abbvie, Bial, and Zambon. B.J. Traynor holds a patent for “Diagnostic and therapeutic implications for the C9orf72 repeat expansion” and has collaborative research agreements with Ionis Pharmaceuticals, Roche, and Optimeos. E.L. Feldman receives consulting fees from Novartis and is an inventor on a patent held by University of Michigan titled, “Methods for Treating Amyotrophic Lateral Sclerosis.” S.A. Goutman is an inventor on a patent held by University of Michigan titled, “Methods for Treating Amyotrophic Lateral Sclerosis.” The other authors declare no competing interests. Go to Neurology.org/NG for full disclosures., (Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Published
2023
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32. Antibody response to the messenger RNA-1273 vaccine (Moderna) in liver transplant recipients.

Author

Cuadrado A, Del Barrio M, Fortea JI, Amigo L, San Segundo D, Rodriguez-Cundin MP, Rebollo MH, Fernandez-Santiago R, Castillo F, Achalandabaso M, Echeverri J, Anderson EJ, Rodríguez-Sanjuan JC, López-Hoyos M, Crespo J, and Fábrega E

Subjects
2019-nCoV Vaccine mRNA-1273, Antibodies, Viral, Antibody Formation, COVID-19 Vaccines adverse effects, Female, Humans, Immunoglobulin G, Male, Middle Aged, RNA, Messenger, SARS-CoV-2, COVID-19 prevention & control, Liver Transplantation adverse effects, Viral Vaccines
Abstract

Different reports have shown the clinical and serologic response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines in preventing coronavirus disease 2019 (COVID-19) in the general population, but few studies have examined these responses in transplant recipients. We assessed the vaccine immunogenicity of two doses (100 μg) of the mRNA-1273 vaccine (Moderna) administered with a 28-day interval in liver transplant recipients (LTRs) at follow-up at the Marques de Valdecilla University Hospital. LTRs without a history of COVID-19 infection were tested for SARS-CoV-2 immunoglobulin G (IgG) antibodies directed against the spike protein (S) a median of 43 days after receiving the second Moderna vaccine dose. Clinical data, including immunosuppressive regimen and routine laboratory data, were obtained from the medical record of each patient up to 3 months before the date of the first vaccination. Factors associated with serologic response were evaluated through logistic regression. In total, 129 LTRs who had anti-S results were included. Most patients were men (n = 99; 76.7%) with a median age of 63 years (interquartile range, 56-68). Alcohol (43.4%) and chronic hepatitis C (18.6%) were the most frequent causes of liver transplantation. A positive anti-S IgG response was observed in 113 LTRs (87.6%; 95% confidence interval [CI], 80.8-92.2). A strong inverse relationship between mycophenolate mofetil use and serologic response was found (odds ratio, 0.07; 95% CI, 0.02-0.26; p = 0.001). Conclusion: Most LTRs develop an immunological response to the Moderna SARS-CoV-2 mRNA-based vaccine. An immunosuppressive regimen that includes mycophenolate predicts a weak serologic response., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Published
2022
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33. Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson's disease.

Author

Brown EE, Blauwendraat C, Trinh J, Rizig M, Nalls MA, Leveille E, Ruskey JA, Jonvik H, Tan MMX, Bandres-Ciga S, Hassin-Baer S, Brockmann K, Infante J, Tolosa E, Ezquerra M, Ben Romdhan S, Benmahdjoub M, Arezki M, Mhiri C, Hardy J, Singleton AB, Alcalay RN, Gasser T, Grosset DG, Williams NM, Pittman A, Gan-Or Z, Fernandez-Santiago R, Brice A, Lesage S, Farrer M, Wood N, and Morris HR

Subjects
Age of Onset, Aged, Cohort Studies, Epistasis, Genetic genetics, Female, Humans, Linkage Disequilibrium genetics, Male, Middle Aged, Parkinson Disease epidemiology, Parkinson Disease ethnology, Risk, Dynamin III genetics, Genetic Association Studies, Genetic Predisposition to Disease genetics, Genetic Variation genetics, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 genetics, Parkinson Disease genetics, R-SNARE Proteins genetics
Abstract

The LRRK2 gene has rare (p.G2019S) and common risk variants for Parkinson's disease (PD). DNM3 has previously been reported as a genetic modifier of the age at onset in PD patients carrying the LRRK2 p.G2019S mutation. We analyzed this effect in a new cohort of LRRK2 p.G2019S heterozygotes (n = 724) and meta-analyzed our data with previously published data (n = 754). VAMP4 is in close proximity to DNM3, and was associated with PD in a recent study, so it is possible that variants in this gene may be important. We also analyzed the effect of VAMP4 rs11578699 on LRRK2 penetrance. Our analysis of DNM3 in previously unpublished data does not show an effect on age at onset in LRRK2 p.G2019S carriers; however, the inter-study heterogeneity may indicate ethnic or population-specific effects of DNM3. There was no evidence for linkage disequilibrium between DNM3 and VAMP4. Analysis of sporadic patients stratified by the risk variant LRRK2 rs10878226 indicates a possible interaction between common variation in LRRK2 and VAMP4 in disease risk., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2021
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34. CCAAT/enhancer binding protein δ is a transcriptional repressor of α-synuclein.

Author

Valente T, Dentesano G, Ezquerra M, Fernandez-Santiago R, Martinez-Martin J, Gallastegui E, Domuro C, Compta Y, Martí MJ, Bachs O, Márquez-Kisinousky L, Straccia M, Solà C, and Saura J

Subjects
Aged, Animals, CCAAT-Enhancer-Binding Protein-delta deficiency, CCAAT-Enhancer-Binding Protein-delta metabolism, Cells, Cultured, Female, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, alpha-Synuclein metabolism, CCAAT-Enhancer-Binding Protein-delta genetics, alpha-Synuclein genetics
Abstract

α-Synuclein is the main component of Lewy bodies, the intracellular protein aggregates representing the histological hallmark of Parkinson's disease. Elevated α-synuclein levels and mutations in SNCA gene are associated with increased risk for Parkinson's disease. Despite this, little is known about the molecular mechanisms regulating SNCA transcription. CCAAT/enhancer binding protein (C/EBP) β and δ are b-zip transcription factors that play distinct roles in neurons and glial cells. C/EBPβ overexpression increases SNCA expression in neuroblastoma cells and putative C/EBPβ and δ binding sites are present in the SNCA genomic region suggesting that these proteins could regulate SNCA transcription. Based on these premises, the goal of this study was to determine if C/EBPβ and δ regulate the expression of SNCA. We first observed that α-synuclein CNS expression was not affected by C/EBPβ deficiency but it was markedly increased in C/EBPδ-deficient mice. This prompted us to characterize further the role of C/EBPδ in SNCA transcription. C/EBPδ absence led to the in vivo increase of α-synuclein in all brain regions analyzed, both at mRNA and protein level, and in primary neuronal cultures. In agreement with this, CEBPD overexpression in neuroblastoma cells and in primary neuronal cultures markedly reduced SNCA expression. ChIP experiments demonstrated C/EBPδ binding to the SNCA genomic region of mice and humans and luciferase experiments showed decreased expression of a reporter gene attributable to C/EBPδ binding to the SNCA promoter. Finally, decreased CEBPD expression was observed in the substantia nigra and in iPSC-derived dopaminergic neurons from Parkinson patients resulting in a significant negative correlation between SNCA and CEBPD levels. This study points to C/EBPδ as an important repressor of SNCA transcription and suggests that reduced C/EBPδ neuronal levels could be a pathogenic factor in Parkinson's disease and other synucleinopathies and C/EBPδ activity a potential pharmacological target for these neurological disorders.

Published
2020
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