α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson’s disease
| Autor: | Ludtmann, Marthe HR, Angelova, Plamena R, Horrocks, Mathew H, Choi, Minee L, Rodrigues, Margarida, Baev, Artyom Y, Berezhnov, Alexey V, Yao, Zhi, Little, Daniel, Banushi, Blerida, Al-Menhali, Afnan Saleh, Ranasinghe, Rohan T, Whiten, Daniel R, Yapom, Ratsuda, Dolt, Karamjit Singh, Devine, Michael J, Gissen, Paul, Kunath, Tilo, Jaganjac, Morana, Pavlov, Evgeny V, Klenerman, David, Abramov, Andrey Y, Gandhi, Sonia |
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| Přispěvatelé: | Devine, Michael J [0000-0001-6076-3382], Gissen, Paul [0000-0002-9712-6122], Kunath, Tilo [0000-0002-8805-7356], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Proteomics
Patch-Clamp Techniques Science Induced Pluripotent Stem Cells neurological disorders Mitochondrial Membrane Transport Proteins Article Permeability Rats Sprague-Dawley Animals Humans lcsh:Science Embryonic Stem Cells Neurons cellular neuroscience Mitochondrial Permeability Transition Pore Parkinson Disease Mitochondrial Proton-Translocating ATPases Coculture Techniques Mitochondria Rats nervous system diseases Mechanisms of disease α-synuclein ATP synthase Parkinson’s disease nervous system alpha-Synuclein lcsh:Q Lipid Peroxidation Reactive Oxygen Species Oxidation-Reduction |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-16 (2018) Ludtmann, M HR, Angelova, P R, Horrocks, M H, Choi, M, Rodrigues, M, Baev, A Y, Berezhnov, A V, Yao, Z, Little, D, Banushi, B, Al-Menhali, A S, Ranasinghe, R T, Whiten, D R, Yapom, R, Singh Dolt, K, Devine, M J, Gissen, P, Kunath, T, Jaganjac, M, Pavlov, E V, Klenerman, D, Abramov, A Y & Gandhi, S 2018, ' α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson’s disease ', Nature Communications, vol. 9, 2293 . https://doi.org/10.1038/s41467-018-04422-2 Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-018-04422-2 |
| Popis: | Protein aggregation causes α-synuclein to switch from its physiological role to a pathological toxic gain of function. Under physiological conditions, monomeric α-synuclein improves ATP synthase efficiency. Here, we report that aggregation of monomers generates beta sheet-rich oligomers that localise to the mitochondria in close proximity to several mitochondrial proteins including ATP synthase. Oligomeric α-synuclein impairs complex I-dependent respiration. Oligomers induce selective oxidation of the ATP synthase beta subunit and mitochondrial lipid peroxidation. These oxidation events increase the probability of permeability transition pore (PTP) opening, triggering mitochondrial swelling, and ultimately cell death. Notably, inhibition of oligomer-induced oxidation prevents the pathological induction of PTP. Inducible pluripotent stem cells (iPSC)-derived neurons bearing SNCA triplication, generate α-synuclein aggregates that interact with the ATP synthase and induce PTP opening, leading to neuronal death. This study shows how the transition of α-synuclein from its monomeric to oligomeric structure alters its functional consequences in Parkinson’s disease. How toxic aggregated forms of α-synuclein lead to neurodegeneration is unclear. Here authors use biophysical and cellular imaging methods to show that specific oligomers of α-synuclein exert effects on mitochondria to induce opening of the permeability transition pore, leading to cell death in Parkinson’s disease. |
| Databáze: | OpenAIRE |
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