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2. Human iPSC-derived microglia carrying the LRRK2-G2019S mutation show a Parkinson’s disease related transcriptional profile and function

Author

Ohtonen, Sohvi, Giudice, Luca, Jäntti, Henna, Fazaludeen, Mohammad Feroze, Shakirzyanova, Anastasia, Gómez-Budia, Mireia, Välimäki, Nelli-Noora, Niskanen, Jonna, Korvenlaita, Nea, Fagerlund, Ilkka, Koistinaho, Jari, Amiry-Moghaddam, Mahmood, Savchenko, Ekaterina, Roybon, Laurent, Lehtonen, Šárka, Korhonen, Paula, and Malm, Tarja

Published
2023
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4. Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome

Author

Peteri, Ulla‐Kaisa, Pitkonen, Juho, de Toma, Ilario, Nieminen, Otso, Utami, Kagistia Hana, Strandin, Tomas M, Corcoran, Padraic, Roybon, Laurent, Vaheri, Antti, Ethell, Iryna, Casarotto, Plinio, Pouladi, Mahmoud A, and Castrén, Maija L

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Intellectual and Developmental Disabilities (IDD), Pediatric, Mental Health, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Fragile X Syndrome, Stem Cell Research, Genetics, Brain Disorders, Neurosciences, Rare Diseases, Stem Cell Research - Induced Pluripotent Stem Cell, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Neurological, Animals, Astrocytes, Autism Spectrum Disorder, Humans, Induced Pluripotent Stem Cells, Mice, Urokinase-Type Plasminogen Activator, astrocyte, fragile X syndrome, neuronal plasticity, urokinase plasminogen activator, Neurology & Neurosurgery
Abstract

The function of astrocytes intertwines with the extracellular matrix, whose neuron and glial cell-derived components shape neuronal plasticity. Astrocyte abnormalities have been reported in the brain of the mouse model for fragile X syndrome (FXS), the most common cause of inherited intellectual disability, and a monogenic cause of autism spectrum disorder. We compared human FXS and control astrocytes generated from human induced pluripotent stem cells and we found increased expression of urokinase plasminogen activator (uPA), which modulates degradation of extracellular matrix. Several pathways associated with uPA and its receptor function were activated in FXS astrocytes. Levels of uPA were also increased in conditioned medium collected from FXS hiPSC-derived astrocyte cultures and correlated inversely with intracellular Ca2+ responses to activation of L-type voltage-gated calcium channels in human astrocytes. Increased uPA augmented neuronal phosphorylation of TrkB within the docking site for the phospholipase-Cγ1 (PLCγ1), indicating effects of uPA on neuronal plasticity. Gene expression changes during neuronal differentiation preceding astrogenesis likely contributed to properties of astrocytes with FXS-specific alterations that showed specificity by not affecting differentiation of adenosine triphosphate (ATP)-responsive astrocyte population. To conclude, our studies identified uPA as an important regulator of astrocyte function and demonstrated that increased uPA in human FXS astrocytes modulated astrocytic responses and neuronal plasticity.

Published
2021

5. Cellular Aging Secretes: a Comparison of Bone-Marrow-Derived and Induced Mesenchymal Stem Cells and Their Secretome Over Long-Term Culture

Author

Marote, Ana, Santos, Diogo, Mendes-Pinheiro, Bárbara, Serre-Miranda, Cláudia, Anjo, Sandra I., Vieira, Joana, Ferreira-Antunes, Filipa, Correia, Joana Sofia, Borges-Pereira, Caroline, Pinho, Andreia G., Campos, Jonas, Manadas, Bruno, Teixeira, Manuel R., Correia-Neves, Margarida, Pinto, Luísa, Costa, Pedro M., Roybon, Laurent, and Salgado, António J.

Published
2023
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8. TNFa hinders FGF4 efficacy to mitigate ALS astrocyte dysfunction and cGAS-STING pathway-induced innate immune reactivity

Author

Velasquez, Erika, primary, savchenko, ekaterina, additional, marmolejo, sara, additional, challuau, desire, additional, aebi, aline, additional, Pomeshchik, Yuriy, additional, Lamas, Nuno, additional, Vihinen, Mauno, additional, Rezeli, melinda, additional, schneider, bernard, additional, Raoul, cedric, additional, and roybon, laurent, additional

Published
2023
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11. Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition

Author

Siebzehnrübl, Florian A., Raber, Kerstin A., Urbach, Yvonne K., Schulze-Krebs, Anja, Canneva, Fabio, Moceri, Sandra, Habermeyer, Johanna, Achoui, Dalila, Gupta, Bhavana, Steindler, Dennis A., Stephan, Michael, Nguyen, Huu Phuc, Bonin, Michael, Riess, Olaf, Bauer, Andreas, Aigner, Ludwig, Couillard-Despres, Sebastien, Paucar, Martin Arce, Svenningsson, Per, Osmand, Alexander, Andreew, Alexander, Zabel, Claus, Weiss, Andreas, Kuhn, Rainer, Moussaoui, Saliha, Blockx, Ines, Van der Linden, Annemie, Cheong, Rachel Y., Roybon, Laurent, Petersén, Åsa, and von Hörsten, Stephan

Published
2018

12. Parkin absence accelerates microtubule aging in dopaminergic neurons

Author

Cartelli, Daniele, Amadeo, Alida, Calogero, Alessandra Maria, Casagrande, Francesca Vittoria Marialuisa, De Gregorio, Carmelita, Gioria, Mariarosa, Kuzumaki, Naoko, Costa, Ilaria, Sassone, Jenny, Ciammola, Andrea, Hattori, Nobutaka, Okano, Hideyuki, Goldwurm, Stefano, Roybon, Laurent, Pezzoli, Gianni, and Cappelletti, Graziella

Published
2018
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14. Cellular alterations identified in pluripotent stem cell-derived midbrain spheroids generated from a female patient with progressive external ophthalmoplegia and parkinsonism who carries a novel variation (p.Q811R) in the POLG1 gene

Author

Chumarina, Margarita, Russ, Kaspar, Azevedo, Carla, Heuer, Andreas, Pihl, Maria, Collin, Anna, Frostner, Eleonor Åsander, Elmer, Eskil, Hyttel, Poul, Cappelletti, Graziella, Zini, Michela, Goldwurm, Stefano, and Roybon, Laurent

Published
2019
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15. Human iPSC-Derived Hippocampal Spheroids: An Innovative Tool for Stratifying Alzheimer Disease Patient-Specific Cellular Phenotypes and Developing Therapies

Author

Pomeshchik, Yuriy, primary, Klementieva, Oxana, additional, Gil, Jeovanis, additional, Martinsson, Isak, additional, Hansen, Marita Grønning, additional, de Vries, Tessa, additional, Sancho-Balsells, Anna, additional, Russ, Kaspar, additional, Savchenko, Ekaterina, additional, Collin, Anna, additional, Vaz, Ana Rita, additional, Bagnoli, Silvia, additional, Nacmias, Benedetta, additional, Rampon, Claire, additional, Sorbi, Sandro, additional, Brites, Dora, additional, Marko-Varga, György, additional, Kokaia, Zaal, additional, Rezeli, Melinda, additional, Gouras, Gunnar K., additional, and Roybon, Laurent, additional

Published
2023
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17. Proteomic analysis across patient iPSC-based models and human post-mortem hippocampal tissue reveals early cellular dysfunction, progression, and prion-like spread of Alzheimer’s disease pathogenesis

Author

Pomeshchik, Yuriy, primary, Velasquez, Erika, additional, Gil, Jeovanis, additional, Klementieva, Oxana, additional, Gidlöf, Ritha, additional, Sydoff, Marie, additional, Bagnoli, Silvia, additional, Nacmias, Benedetta, additional, Sorbi, Sandro, additional, Westergren-Thorsson, Gunilla, additional, Gouras, Gunnar K., additional, Rezeli, Melinda, additional, and Roybon, Laurent, additional

Published
2023
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19. Cellular Aging Secretes: a Comparison of Bone-Marrow-Derived and Induced Mesenchymal Stem Cells and Their Secretome Over Long-Term Culture

Author

Marote, Ana, primary, Santos, Diogo, additional, Mendes-Pinheiro, Bárbara, additional, Serre-Miranda, Cláudia, additional, Anjo, Sandra I., additional, Vieira, Joana, additional, Ferreira-Antunes, Filipa, additional, Correia, Joana Sofia, additional, Borges-Pereira, Caroline, additional, Pinho, Andreia G., additional, Campos, Jonas, additional, Manadas, Bruno, additional, Teixeira, Manuel R., additional, Correia-Neves, Margarida, additional, Pinto, Luísa, additional, Costa, Pedro M., additional, Roybon, Laurent, additional, and Salgado, António J., additional

Published
2022
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21. Parkinsons disease and multiple system atrophy patient iPSC-derived oligodendrocytes exhibit alpha-synuclein-induced changes in maturation and immune reactive properties

Author

Azevedo, Carla, Teku, Gabriel, Pomeshchik, Yuriy, Reyes, Juan F., Chumarina, Margarita, Russ, Kaspar, Savchenko, Ekaterina, Hammarberg, Anna, Lamas, Nuno Jorge, Collin, Anna, Gouras, Gunnar K., Klementieva, Oxana, Hallbeck, Martin, Taipa, Ricardo, Vihinen, Mauno, Roybon, Laurent, Azevedo, Carla, Teku, Gabriel, Pomeshchik, Yuriy, Reyes, Juan F., Chumarina, Margarita, Russ, Kaspar, Savchenko, Ekaterina, Hammarberg, Anna, Lamas, Nuno Jorge, Collin, Anna, Gouras, Gunnar K., Klementieva, Oxana, Hallbeck, Martin, Taipa, Ricardo, Vihinen, Mauno, and Roybon, Laurent

Abstract

Limited evidence has shed light on how aSYN proteins affect the oligodendrocyte phenotype and pathogenesis in synucleinopathies that include Parkinsons disease (PD) and multiple system atrophy (MSA). Here, we investigated early transcriptomic changes within PD and MSA O4(+) oligodendrocyte lineage cells (OLCs) generated from patient-induced pluripotent stem cells (iPSCs). We found impaired maturation of PD and MSA O4(+) OLCs compared to controls. This phenotype was associated with changes in the human leukocyte antigen (HLA) genes, the immunoproteasome subunit PSMB9, and the complement component C4b for aSYN p.A53T and MSA O4(+) OLCs, but not in SNCA(trip) O4(+) OLCs despite high levels of aSYN assembly formation. Moreover, SNCA overexpression resulted in the development of O4(+) OLCs, whereas exogenous treatment with aSYN species led to significant toxicity. Notably, transcriptome profiling of genes encoding proteins forming Lewy bodies and glial cytoplasmic inclusions revealed clustering of PD aSYN p.A53T O4(+) OLCs with MSA O4(+) OLCs. Our work identifies early phenotypic and pathogenic changes within human PD and MSA O4(+) OLCs., Funding Agencies|Telethon ItalyFondazione Telethon [GTB12001]; Swedish private foundations (Holger Crafoord Foundation); Swedish private foundations (Shaking Generation Foundation); Swedish private foundations (Petrus and Augusta Hedlunds Foundation); Swedish private foundations (Ake Wibergs Foundation); Swedish private foundations (Greta och Johan Kocks Foundation); Swedish Research CouncilSwedish Research CouncilEuropean Commission [VR-201503684, VR-2121-02284, VR-2015-02510]; Brainstem-Stem Cell Center for Excellence in Neurology - Innovation Fund Denmark; Olav Thon Foundation in Norway; European UnionEuropean Commission [2015-06798]

Published
2022
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23. Parkinson’s disease and multiple system atrophy patient iPSC-derived oligodendrocytes exhibit alpha-synuclein–induced changes in maturation and immune reactive properties

Author

Azevedo, Carla, primary, Teku, Gabriel, additional, Pomeshchik, Yuriy, additional, Reyes, Juan F., additional, Chumarina, Margarita, additional, Russ, Kaspar, additional, Savchenko, Ekaterina, additional, Hammarberg, Anna, additional, Lamas, Nuno Jorge, additional, Collin, Anna, additional, Gouras, Gunnar K., additional, Klementieva, Oxana, additional, Hallbeck, Martin, additional, Taipa, Ricardo, additional, Vihinen, Mauno, additional, and Roybon, Laurent, additional

Published
2022
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25. α-Synuclein is a Novel Microtubule Dynamase

Author

Cartelli, Daniele, Aliverti, Alessandro, Barbiroli, Alberto, Santambrogio, Carlo, Ragg, Enzio M., Casagrande, Francesca V.M., Cantele, Francesca, Beltramone, Silvia, Marangon, Jacopo, De Gregorio, Carmelita, Pandini, Vittorio, Emanuele, Marco, Chieregatti, Evelina, Pieraccini, Stefano, Holmqvist, Staffan, Bubacco, Luigi, Roybon, Laurent, Pezzoli, Gianni, Grandori, Rita, Arnal, Isabelle, and Cappelletti, Graziella

Published
2016
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27. Human iPSC-derived hippocampal spheroids: An innovative tool for stratifying Alzheimer disease patient-specific cellular phenotypes and developing therapies

Author

Pomeshchik, Yuriy, primary, Klementieva, Oxana, additional, Gil, Jeovanis, additional, Martinsson, Isak, additional, Hansen, Marita Grønning, additional, de Vries, Tessa, additional, Sancho-Balsells, Anna, additional, Russ, Kaspar, additional, Savchenko, Ekaterina, additional, Collin, Anna, additional, Vaz, Ana Rita, additional, Bagnoli, Silvia, additional, Nacmias, Benedetta, additional, Rampon, Claire, additional, Sorbi, Sandro, additional, Brites, Dora, additional, Marko-Varga, György, additional, Kokaia, Zaal, additional, Rezeli, Melinda, additional, Gouras, Gunnar K., additional, and Roybon, Laurent, additional

Published
2021
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29. TNF-α and α-synuclein fibrils differently regulate human astrocyte immune reactivity and impair mitochondrial respiration

Author

Russ, Kaspar, Teku, Gabriel, Bousset, Luc, Redeker, Virginie, Piel, Sara, Savchenko, Ekaterina, Pomeshchik, Yuriy, Savistchenko, Jimmy, Stummann, Tina C., Azevedo, Carla, Collin, Anna, Goldwurm, Stefano, Fog, Karina, Elmer, Eskil, Vihinen, Mauno, Melki, Ronald, Roybon, Laurent, Lund University [Lund], Biomedical Centre [Lund] (BMC), Centre National de la Recherche Scientifique (CNRS), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Clinical Sciences [Lund], Immunology Section, Department of Experimental Medical Sciences, Medical Faculty, H. Lundbeck A/S [Valby, Denmark], Department of Clinical Genetics and Pathology, Centro Parkinson/Parkinson Institute, ASST ‘‘Gaetano Pini/CTO,’, ANR-14-JPCD-0002,Neutargets,Targeting the propagation of pathogenic protein assemblies in neurodegenerative disease(2014), ANR-15-JPWG-0012,SYNACTION,Unravelling the pathophysiological role of alpha-synuclein aggregation, transmission and neuroinflammation in neurodegeneration(2015), ANR-15-JPWG-0007,MADGIC,Generation of Improved cellular and animal Models for identification of disease phenotype and new therapeutic targets of Alzheimer?s Disease(2015), European Project: (grant No 116060),IMPRiND, and Université Paris-Saclay-Institut de Biologie François JACOB (JACOB)

Subjects
Ubiquitin-Protein Ligases, alpha-synuclein, HLA genes, [SDV]Life Sciences [q-bio], Cell Respiration, Induced Pluripotent Stem Cells, Adenosine Triphosphate, Humans, Amino Acid Sequence, lcsh:QH301-705.5, Antigen Presentation, iPSC, Tumor Necrosis Factor-alpha, Cell Membrane, astrocytes, Parkinson Disease, Mitochondria, Molecular Weight, reactivity, Phenotype, lcsh:Biology (General), Parkinson’s disease, Cytokines, Inflammation Mediators, Peptides, HLA-DRB1 Chains
Abstract

International audience; Here, we examine the cellular changes triggered by tumor necrosis factor alpha (TNF-a) and different alphasynuclein(aSYN) species in astrocytes derived from induced pluripotent stem cells. Human astrocytestreated with TNF-a display a strong reactive pro-inflammatory phenotype with upregulation of pro-inflammatorygene networks, activation of the nuclear factor kB (NF-kB) pathway, and release of pro-inflammatorycytokines, whereas those treated with high-molecular-weight aSYN fibrils acquire a reactive antigen(cross)-presenting phenotype with upregulation of major histocompatibility complex (MHC) genes andincreased human leukocyte antigen (HLA) molecules at the cell surface. Surprisingly, the cell surface locationof MHC proteins is abrogated by larger F110 fibrillar polymorphs, despite the upregulation of MHC genes.Interestingly, TNF-a and aSYN fibrils compete to drive the astrocyte immune reactive response. The astrocyteimmune responses are accompanied by an impaired mitochondrial respiration, which is exacerbatedin Parkinson’s disease (PD) astrocytes. Our data provide evidence for astrocytic involvement in PD pathogenesisand reveal their complex immune reactive responses to exogenous stressors.

Published
2021

30. Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome

Author

Peteri, Ulla-Kaisa, Pitkonen, Juho, de Toma, Ilario, Nieminen, Otso, Utami, Kagistia Hana, Strandin, Tomas M., Corcoran, Pádraic, Roybon, Laurent, Vaheri, Antti, Ethell, Iryna, Casarotto, Plinio, Pouladi, Mahmoud A., Castren, Maija L., Peteri, Ulla-Kaisa, Pitkonen, Juho, de Toma, Ilario, Nieminen, Otso, Utami, Kagistia Hana, Strandin, Tomas M., Corcoran, Pádraic, Roybon, Laurent, Vaheri, Antti, Ethell, Iryna, Casarotto, Plinio, Pouladi, Mahmoud A., and Castren, Maija L.

Abstract

The function of astrocytes intertwines with the extracellular matrix, whose neuron and glial cell-derived components shape neuronal plasticity. Astrocyte abnormalities have been reported in the brain of the mouse model for fragile X syndrome (FXS), the most common cause of inherited intellectual disability, and a monogenic cause of autism spectrum disorder. We compared human FXS and control astrocytes generated from human induced pluripotent stem cells and we found increased expression of urokinase plasminogen activator (uPA), which modulates degradation of extracellular matrix. Several pathways associated with uPA and its receptor function were activated in FXS astrocytes. Levels of uPA were also increased in conditioned medium collected from FXS hiPSC-derived astrocyte cultures and correlated inversely with intracellular Ca2+ responses to activation of L-type voltage-gated calcium channels in human astrocytes. Increased uPA augmented neuronal phosphorylation of TrkB within the docking site for the phospholipase-C gamma 1 (PLC gamma 1), indicating effects of uPA on neuronal plasticity. Gene expression changes during neuronal differentiation preceding astrogenesis likely contributed to properties of astrocytes with FXS-specific alterations that showed specificity by not affecting differentiation of adenosine triphosphate (ATP)-responsive astrocyte population. To conclude, our studies identified uPA as an important regulator of astrocyte function and demonstrated that increased uPA in human FXS astrocytes modulated astrocytic responses and neuronal plasticity.

Published
2021
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34. Unique signatures of stress-induced senescent human astrocytes

Author

Simmnacher, Katrin, primary, Krach, Florian, additional, Schneider, Yanni, additional, Alecu, Julian E., additional, Mautner, Lena, additional, Klein, Paulina, additional, Roybon, Laurent, additional, Prots, Iryna, additional, Xiang, Wei, additional, and Winner, Beate, additional

Published
2020
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35. Human iPSC-Derived Hippocampal Spheroids: An Innovative Tool for Stratifying Alzheimer Disease Patient-Specific Cellular Phenotypes and Developing Therapies

Author

Pomeshchik, Yuriy, primary, Klementieva, Oxana, additional, Gil, Jeovanis, additional, Martinsson, Isak, additional, Hansen, Marita Grønning, additional, de Vries, Tessa, additional, Sancho-Balsells, Anna, additional, Russ, Kaspar, additional, Savchenko, Ekaterina, additional, Collin, Anna, additional, Vaz, Ana Rita, additional, Bagnoli, Silvia, additional, Nacmias, Benedetta, additional, Rampon, Claire, additional, Sorbi, Sandro, additional, Brites, Dora, additional, Marko-Varga, György, additional, Kokaia, Zaal, additional, Rezeli, Melinda, additional, Gouras, Gunnar K., additional, and Roybon, Laurent, additional

Published
2020
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36. Demonstration of brain region-specific neuronal vulnerability in human iPSC-based model of familial Parkinson’s disease

Author

Brazdis, Razvan-Marius, primary, Alecu, Julian E, primary, Marsch, Daniel, primary, Dahms, Annika, primary, Simmnacher, Katrin, primary, Lörentz, Sandra, primary, Brendler, Anna, primary, Schneider, Yanni, primary, Marxreiter, Franz, primary, Roybon, Laurent, primary, Winner, Beate, primary, Xiang, Wei, primary, and Prots, Iryna, primary

Published
2020
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43. PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived Neurons

Author

Bogetofte, Helle, Jensen, Pia, Ryding, Matias, Schmidt, Sissel I, Okarmus, Justyna, Ritter, Louise, Worm, Christina S, Hohnholt, Michaela C, Azevedo, Carla, Roybon, Laurent, Bak, Lasse K, Waagepetersen, Helle, Ryan, Brent J, Wade-Martins, Richard, Larsen, Martin R, Meyer, Morten, Bogetofte, Helle, Jensen, Pia, Ryding, Matias, Schmidt, Sissel I, Okarmus, Justyna, Ritter, Louise, Worm, Christina S, Hohnholt, Michaela C, Azevedo, Carla, Roybon, Laurent, Bak, Lasse K, Waagepetersen, Helle, Ryan, Brent J, Wade-Martins, Richard, Larsen, Martin R, and Meyer, Morten

Abstract

The protein parkin, encoded by the PARK2 gene, is vital for mitochondrial homeostasis, and although it has been implicated in Parkinson's disease (PD), the disease mechanisms remain unclear. We have applied mass spectrometry-based proteomics to investigate the effects of parkin dysfunction on the mitochondrial proteome in human isogenic induced pluripotent stem cell-derived neurons with and without PARK2 knockout (KO). The proteomic analysis quantified nearly 60% of all mitochondrial proteins, 119 of which were dysregulated in neurons with PARK2 KO. The protein changes indicated disturbances in oxidative stress defense, mitochondrial respiration and morphology, cell cycle control, and cell viability. Structural and functional analyses revealed an increase in mitochondrial area and the presence of elongated mitochondria as well as impaired glycolysis and lactate-supported respiration, leading to an impaired cell survival in PARK2 KO neurons. This adds valuable insight into the effect of parkin dysfunction in human neurons and provides knowledge of disease-related pathways that can potentially be targeted for therapeutic intervention.

Published
2019

44. NF‐E2‐related factor 2 activation boosts antioxidant defenses and ameliorates inflammatory and amyloid properties in human Presenilin‐1 mutated Alzheimer's disease astrocytes

Author

Oksanen, Minna, primary, Hyötyläinen, Ida, additional, Trontti, Kalevi, additional, Rolova, Taisia, additional, Wojciechowski, Sara, additional, Koskuvi, Marja, additional, Viitanen, Matti, additional, Levonen, Anna‐Liisa, additional, Hovatta, Iiris, additional, Roybon, Laurent, additional, Lehtonen, Šárka, additional, Kanninen, Katja M., additional, Hämäläinen, Riikka H., additional, and Koistinaho, Jari, additional

Published
2019
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45. PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived Neurons

Author

Bogetofte, Helle, primary, Jensen, Pia, additional, Ryding, Matias, additional, Schmidt, Sissel I., additional, Okarmus, Justyna, additional, Ritter, Louise, additional, Worm, Christina S., additional, Hohnholt, Michaela C., additional, Azevedo, Carla, additional, Roybon, Laurent, additional, Bak, Lasse K., additional, Waagepetersen, Helle, additional, Ryan, Brent J., additional, Wade-Martins, Richard, additional, Larsen, Martin R., additional, and Meyer, Morten, additional

Published
2019
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46. Generation of an induced pluripotent stem cell line (CSC-46) from a patient with Parkinson's disease carrying a novel p.R301C mutation in the GBA gene

Author

Gustavsson, Nadja, primary, Marote, Ana, additional, Pomeshchik, Yuriy, additional, Russ, Kaspar, additional, Azevedo, Carla, additional, Chumarina, Margarita, additional, Goldwurm, Stefano, additional, Collin, Anna, additional, Pinto, Luisa, additional, Salgado, António J., additional, Klementieva, Oxana, additional, Roybon, Laurent, additional, and Savchenko, Ekaterina, additional

Published
2019
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47. Human Astrocytes Transfer Aggregated Alpha-Synuclein via Tunneling Nanotubes

Author

Rostami, Jinar, Holmqvist, Staffan, Lindström, Veronica, Sigvardson, Jessica, Westermark, Gunilla T, Ingelsson, Martin, Bergström, Joakim, Roybon, Laurent, Erlandsson, Anna, Holmqvist, Staffan [0000-0001-6709-6666], and Apollo - University of Cambridge Repository

Subjects
Nanotubes, Neurologi, animal diseases, alpha-synuclein, astrocytes, Cell Communication, nervous system diseases, mitochondria, tunneling nanotubes, lysosomes, Neurology, nervous system, Neurobiology of Disease, Astrocytes, trans-Golgi, Humans, Research Articles, Cells, Cultured, Embryonic Stem Cells
Abstract

Many lines of evidence suggest that the Parkinson's disease (PD)-related protein α-synuclein (α-SYN) can propagate from cell to cell in a prion-like manner. However, the cellular mechanisms behind the spreading remain elusive. Here, we show that human astrocytes derived from embryonic stem cells actively transfer aggregated α-SYN to nearby astrocytes via direct contact and tunneling nanotubes (TNTs). Failure in the astrocytes' lysosomal digestion of excess α-SYN oligomers results in α-SYN deposits in the trans-Golgi network followed by endoplasmic reticulum swelling and mitochondrial disturbances. The stressed astrocytes respond by conspicuously sending out TNTs, enabling intercellular transfer of α-SYN to healthy astrocytes, which in return deliver mitochondria, indicating a TNT-mediated rescue mechanism. Using a pharmacological approach to inhibit TNT formation, we abolished the transfer of both α-SYN and mitochondria. Together, our results highlight the role of astrocytes in α-SYN cell-to-cell transfer, identifying possible pathophysiological events in the PD brain that could be of therapeutic relevance. SIGNIFICANCE STATEMENT Astrocytes are the major cell type in the brain, yet their role in Parkinson's disease progression remains elusive. Here, we show that human astrocytes actively transfer aggregated α-synuclein (α-SYN) to healthy astrocytes via direct contact and tunneling nanotubes (TNTs), rather than degrade it. The astrocytes engulf large amounts of oligomeric α-SYN that are subsequently stored in the trans-Golgi network region. The accumulation of α-SYN in the astrocytes affects their lysosomal machinery and induces mitochondrial damage. The stressed astrocytes respond by sending out TNTs, enabling intercellular transfer of α-SYN to healthy astrocytes. Our findings highlight an unexpected role of astrocytes in the propagation of α-SYN pathology via TNTs, revealing astrocytes as a potential target for therapeutic intervention.

Published
2017

48. NF‐E2‐related factor 2 activation boosts antioxidant defenses and ameliorates inflammatory and amyloid properties in human Presenilin‐1 mutated Alzheimer's disease astrocytes.

Author

Oksanen, Minna, Hyötyläinen, Ida, Trontti, Kalevi, Rolova, Taisia, Wojciechowski, Sara, Koskuvi, Marja, Viitanen, Matti, Levonen, Anna‐Liisa, Hovatta, Iiris, Roybon, Laurent, Lehtonen, Šárka, Kanninen, Katja M., Hämäläinen, Riikka H., and Koistinaho, Jari

Published
2020
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