Drp-1 dependent mitochondrial fragmentation and protective autophagy in dopaminergic SH-SY5Y cells overexpressing alpha-synuclein
Parkinson's disease is a neurodegenerative movement disorder caused by the loss of dopaminergic neurons from substantia nigra. It is characterized by the accumulation of aggregated α-synuclein as the major component of the Lewy bodies. Additional common features of this disease are the mitochon...
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todo:paper_10447431_v88_n_p107_Martinez2023-10-03T15:58:19Z Drp-1 dependent mitochondrial fragmentation and protective autophagy in dopaminergic SH-SY5Y cells overexpressing alpha-synuclein Martinez, J.H. Alaimo, A. Gorojod, R.M. Porte Alcon, S. Fuentes, F. Coluccio Leskow, F. Kotler, M.L. alpha-synuclein autophagy mitochondria mitochondrial dynamics mitophagy Parkinson's Disease alpha synuclein dynamin related protein 1 hybrid protein mitochondrial protein optic atrophy 1 protein reactive oxygen metabolite unclassified drug alpha synuclein DNM1L protein, human guanosine triphosphatase microtubule associated protein mitochondrial protein OPA1 protein, human SNCA protein, human Article autophagy cell death cell protection cell survival cell viability controlled study cytotoxicity disorders of mitochondrial functions dopaminergic nerve cell gene overexpression human human cell in vitro study mitochondrial dynamics mitochondrial fragmentation mitophagy Parkinson disease priority journal SH-SY5Y cell line wild type autophagy dopaminergic nerve cell genetics metabolism mitochondrion physiology substantia nigra tumor cell line alpha-Synuclein Autophagy Cell Line, Tumor Dopaminergic Neurons GTP Phosphohydrolases Humans Microtubule-Associated Proteins Mitochondria Mitochondrial Degradation Mitochondrial Dynamics Mitochondrial Proteins Parkinson Disease Substantia Nigra Parkinson's disease is a neurodegenerative movement disorder caused by the loss of dopaminergic neurons from substantia nigra. It is characterized by the accumulation of aggregated α-synuclein as the major component of the Lewy bodies. Additional common features of this disease are the mitochondrial dysfunction and the activation/inhibition of autophagy both events associated to the intracellular accumulation of α-synuclein. The mechanism by which these events contribute to neural degeneration remains unknown. In the present work we investigated the effect of α-synuclein on mitochondrial dynamics and autophagy/mitophagy in SH-SY5Y cells, an in vitro model of Parkinson disease. We demonstrated that overexpression of wild type α-synuclein causes moderated toxicity, ROS generation and mitochondrial dysfunction. In addition, α-synuclein induces the mitochondrial fragmentation on a Drp-1-dependent fashion. Overexpression of the fusion protein Opa-1 prevented both mitochondrial fragmentation and cytotoxicity. On the other hand, cells expressing α-synuclein showed activated autophagy and particularly mitophagy. Employing a genetic strategy we demonstrated that autophagy is triggered in order to protect cells from α-synuclein-induced cell death. Our results clarify the role of Opa-1 and Drp-1 in mitochondrial dynamics and cell survival, a controversial α-synuclein research issue. The findings presented point to the relevance of mitochondrial homeostasis and autophagy in the pathogenesis of PD. Better understanding of the molecular interaction between these processes could give rise to novel therapeutic methods for PD prevention and amelioration. © 2018 Elsevier Inc. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_10447431_v88_n_p107_Martinez |
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Universidad de Buenos Aires |
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I-28 |
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R-134 |
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Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
alpha-synuclein autophagy mitochondria mitochondrial dynamics mitophagy Parkinson's Disease alpha synuclein dynamin related protein 1 hybrid protein mitochondrial protein optic atrophy 1 protein reactive oxygen metabolite unclassified drug alpha synuclein DNM1L protein, human guanosine triphosphatase microtubule associated protein mitochondrial protein OPA1 protein, human SNCA protein, human Article autophagy cell death cell protection cell survival cell viability controlled study cytotoxicity disorders of mitochondrial functions dopaminergic nerve cell gene overexpression human human cell in vitro study mitochondrial dynamics mitochondrial fragmentation mitophagy Parkinson disease priority journal SH-SY5Y cell line wild type autophagy dopaminergic nerve cell genetics metabolism mitochondrion physiology substantia nigra tumor cell line alpha-Synuclein Autophagy Cell Line, Tumor Dopaminergic Neurons GTP Phosphohydrolases Humans Microtubule-Associated Proteins Mitochondria Mitochondrial Degradation Mitochondrial Dynamics Mitochondrial Proteins Parkinson Disease Substantia Nigra |
| spellingShingle |
alpha-synuclein autophagy mitochondria mitochondrial dynamics mitophagy Parkinson's Disease alpha synuclein dynamin related protein 1 hybrid protein mitochondrial protein optic atrophy 1 protein reactive oxygen metabolite unclassified drug alpha synuclein DNM1L protein, human guanosine triphosphatase microtubule associated protein mitochondrial protein OPA1 protein, human SNCA protein, human Article autophagy cell death cell protection cell survival cell viability controlled study cytotoxicity disorders of mitochondrial functions dopaminergic nerve cell gene overexpression human human cell in vitro study mitochondrial dynamics mitochondrial fragmentation mitophagy Parkinson disease priority journal SH-SY5Y cell line wild type autophagy dopaminergic nerve cell genetics metabolism mitochondrion physiology substantia nigra tumor cell line alpha-Synuclein Autophagy Cell Line, Tumor Dopaminergic Neurons GTP Phosphohydrolases Humans Microtubule-Associated Proteins Mitochondria Mitochondrial Degradation Mitochondrial Dynamics Mitochondrial Proteins Parkinson Disease Substantia Nigra Martinez, J.H. Alaimo, A. Gorojod, R.M. Porte Alcon, S. Fuentes, F. Coluccio Leskow, F. Kotler, M.L. Drp-1 dependent mitochondrial fragmentation and protective autophagy in dopaminergic SH-SY5Y cells overexpressing alpha-synuclein |
| topic_facet |
alpha-synuclein autophagy mitochondria mitochondrial dynamics mitophagy Parkinson's Disease alpha synuclein dynamin related protein 1 hybrid protein mitochondrial protein optic atrophy 1 protein reactive oxygen metabolite unclassified drug alpha synuclein DNM1L protein, human guanosine triphosphatase microtubule associated protein mitochondrial protein OPA1 protein, human SNCA protein, human Article autophagy cell death cell protection cell survival cell viability controlled study cytotoxicity disorders of mitochondrial functions dopaminergic nerve cell gene overexpression human human cell in vitro study mitochondrial dynamics mitochondrial fragmentation mitophagy Parkinson disease priority journal SH-SY5Y cell line wild type autophagy dopaminergic nerve cell genetics metabolism mitochondrion physiology substantia nigra tumor cell line alpha-Synuclein Autophagy Cell Line, Tumor Dopaminergic Neurons GTP Phosphohydrolases Humans Microtubule-Associated Proteins Mitochondria Mitochondrial Degradation Mitochondrial Dynamics Mitochondrial Proteins Parkinson Disease Substantia Nigra |
| description |
Parkinson's disease is a neurodegenerative movement disorder caused by the loss of dopaminergic neurons from substantia nigra. It is characterized by the accumulation of aggregated α-synuclein as the major component of the Lewy bodies. Additional common features of this disease are the mitochondrial dysfunction and the activation/inhibition of autophagy both events associated to the intracellular accumulation of α-synuclein. The mechanism by which these events contribute to neural degeneration remains unknown. In the present work we investigated the effect of α-synuclein on mitochondrial dynamics and autophagy/mitophagy in SH-SY5Y cells, an in vitro model of Parkinson disease. We demonstrated that overexpression of wild type α-synuclein causes moderated toxicity, ROS generation and mitochondrial dysfunction. In addition, α-synuclein induces the mitochondrial fragmentation on a Drp-1-dependent fashion. Overexpression of the fusion protein Opa-1 prevented both mitochondrial fragmentation and cytotoxicity. On the other hand, cells expressing α-synuclein showed activated autophagy and particularly mitophagy. Employing a genetic strategy we demonstrated that autophagy is triggered in order to protect cells from α-synuclein-induced cell death. Our results clarify the role of Opa-1 and Drp-1 in mitochondrial dynamics and cell survival, a controversial α-synuclein research issue. The findings presented point to the relevance of mitochondrial homeostasis and autophagy in the pathogenesis of PD. Better understanding of the molecular interaction between these processes could give rise to novel therapeutic methods for PD prevention and amelioration. © 2018 Elsevier Inc. |
| format |
JOUR |
| author |
Martinez, J.H. Alaimo, A. Gorojod, R.M. Porte Alcon, S. Fuentes, F. Coluccio Leskow, F. Kotler, M.L. |
| author_facet |
Martinez, J.H. Alaimo, A. Gorojod, R.M. Porte Alcon, S. Fuentes, F. Coluccio Leskow, F. Kotler, M.L. |
| author_sort |
Martinez, J.H. |
| title |
Drp-1 dependent mitochondrial fragmentation and protective autophagy in dopaminergic SH-SY5Y cells overexpressing alpha-synuclein |
| title_short |
Drp-1 dependent mitochondrial fragmentation and protective autophagy in dopaminergic SH-SY5Y cells overexpressing alpha-synuclein |
| title_full |
Drp-1 dependent mitochondrial fragmentation and protective autophagy in dopaminergic SH-SY5Y cells overexpressing alpha-synuclein |
| title_fullStr |
Drp-1 dependent mitochondrial fragmentation and protective autophagy in dopaminergic SH-SY5Y cells overexpressing alpha-synuclein |
| title_full_unstemmed |
Drp-1 dependent mitochondrial fragmentation and protective autophagy in dopaminergic SH-SY5Y cells overexpressing alpha-synuclein |
| title_sort |
drp-1 dependent mitochondrial fragmentation and protective autophagy in dopaminergic sh-sy5y cells overexpressing alpha-synuclein |
| url |
http://hdl.handle.net/20.500.12110/paper_10447431_v88_n_p107_Martinez |
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| _version_ |
1807321934591950848 |