DC Field | Value | Language |
---|---|---|
dc.contributor.author | Choi, Minee L. | ko |
dc.contributor.author | Chappard, Alexandre | ko |
dc.contributor.author | Singh, Bhanu P. | ko |
dc.contributor.author | Maclachlan, Catherine | ko |
dc.contributor.author | Rodrigues, Margarida | ko |
dc.contributor.author | Fedotova, Evgenia | ko |
dc.contributor.author | Berezhnov, Alexey, V | ko |
dc.contributor.author | De, Suman | ko |
dc.contributor.author | Peddie, Chris | ko |
dc.contributor.author | Athauda, Dilan | ko |
dc.contributor.author | Virdi, Gurvir S. | ko |
dc.contributor.author | Zhang, Weijia | ko |
dc.contributor.author | Evans, James R. | ko |
dc.contributor.author | Wernick, Anna | ko |
dc.contributor.author | Zanjani, Zeinab Shadman | ko |
dc.contributor.author | Angelova, Plamena R. | ko |
dc.contributor.author | Esteras, Noemi | ko |
dc.contributor.author | Vinikurov, Andrey | ko |
dc.contributor.author | Morris, Katie | ko |
dc.contributor.author | Jeacock, Kiani | ko |
dc.contributor.author | Tosatto, Laura | ko |
dc.contributor.author | Little, Daniel | ko |
dc.contributor.author | Gissen, Paul | ko |
dc.contributor.author | Clarke, David J. | ko |
dc.contributor.author | Kunath, Tilo | ko |
dc.contributor.author | Collinson, Lucy | ko |
dc.contributor.author | Klenerman, David | ko |
dc.contributor.author | Abramov, Andrey Y. | ko |
dc.contributor.author | Horrocks, Mathew H. | ko |
dc.contributor.author | Gandhi, Sonia | ko |
dc.date.accessioned | 2023-02-06T02:00:11Z | - |
dc.date.available | 2023-02-06T02:00:11Z | - |
dc.date.created | 2023-02-06 | - |
dc.date.created | 2023-02-06 | - |
dc.date.issued | 2022-09 | - |
dc.identifier.citation | NATURE NEUROSCIENCE, v.25, no.9, pp.1134 - 1148 | - |
dc.identifier.issn | 1097-6256 | - |
dc.identifier.uri | http://hdl.handle.net/10203/305021 | - |
dc.description.abstract | Aggregation of alpha-synuclein (alpha-Syn) drives Parkinson's disease (PD), although the initial stages of self-assembly and structural conversion have not been directly observed inside neurons. In this study, we tracked the intracellular conformational states of alpha-Syn using a single-molecule Forster resonance energy transfer (smFRET) biosensor, and we show here that alpha-Syn converts from a monomeric state into two distinct oligomeric states in neurons in a concentration-dependent and sequence-specific manner. Three-dimensional FRET-correlative light and electron microscopy (FRET-CLEM) revealed that intracellular seeding events occur preferentially on membrane surfaces, especially at mitochondrial membranes. The mitochondrial lipid cardiolipin triggers rapid oligomerization of A53T alpha-Syn, and cardiolipin is sequestered within aggregating lipid-protein complexes. Mitochondrial aggregates impair complex I activity and increase mitochondrial reactive oxygen species (ROS) generation, which accelerates the oligomerization of A53T alpha-Syn and causes permeabilization of mitochondrial membranes and cell death. These processes were also observed in induced pluripotent stem cell (iPSC)-derived neurons harboring A53T mutations from patients with PD. Our study highlights a mechanism of de novo alpha-Syn oligomerization at mitochondrial membranes and subsequent neuronal toxicity. This study tracked the initial self-assembly, oligomerization and structural conversion of alpha-synuclein inside neurons. Early seeding events occur on mitochondrial membranes, where oligomerization induces mitochondrial dysfunction and neuronal loss. | - |
dc.language | English | - |
dc.publisher | NATURE PORTFOLIO | - |
dc.title | Pathological structural conversion of alpha-synuclein at the mitochondria induces neuronal toxicity | - |
dc.type | Article | - |
dc.identifier.wosid | 000847656000006 | - |
dc.identifier.scopusid | 2-s2.0-85137745367 | - |
dc.type.rims | ART | - |
dc.citation.volume | 25 | - |
dc.citation.issue | 9 | - |
dc.citation.beginningpage | 1134 | - |
dc.citation.endingpage | 1148 | - |
dc.citation.publicationname | NATURE NEUROSCIENCE | - |
dc.identifier.doi | 10.1038/s41593-022-01140-3 | - |
dc.contributor.localauthor | Choi, Minee L. | - |
dc.contributor.nonIdAuthor | Chappard, Alexandre | - |
dc.contributor.nonIdAuthor | Singh, Bhanu P. | - |
dc.contributor.nonIdAuthor | Maclachlan, Catherine | - |
dc.contributor.nonIdAuthor | Rodrigues, Margarida | - |
dc.contributor.nonIdAuthor | Fedotova, Evgenia | - |
dc.contributor.nonIdAuthor | Berezhnov, Alexey, V | - |
dc.contributor.nonIdAuthor | De, Suman | - |
dc.contributor.nonIdAuthor | Peddie, Chris | - |
dc.contributor.nonIdAuthor | Athauda, Dilan | - |
dc.contributor.nonIdAuthor | Virdi, Gurvir S. | - |
dc.contributor.nonIdAuthor | Zhang, Weijia | - |
dc.contributor.nonIdAuthor | Evans, James R. | - |
dc.contributor.nonIdAuthor | Wernick, Anna | - |
dc.contributor.nonIdAuthor | Zanjani, Zeinab Shadman | - |
dc.contributor.nonIdAuthor | Angelova, Plamena R. | - |
dc.contributor.nonIdAuthor | Esteras, Noemi | - |
dc.contributor.nonIdAuthor | Vinikurov, Andrey | - |
dc.contributor.nonIdAuthor | Morris, Katie | - |
dc.contributor.nonIdAuthor | Jeacock, Kiani | - |
dc.contributor.nonIdAuthor | Tosatto, Laura | - |
dc.contributor.nonIdAuthor | Little, Daniel | - |
dc.contributor.nonIdAuthor | Gissen, Paul | - |
dc.contributor.nonIdAuthor | Clarke, David J. | - |
dc.contributor.nonIdAuthor | Kunath, Tilo | - |
dc.contributor.nonIdAuthor | Collinson, Lucy | - |
dc.contributor.nonIdAuthor | Klenerman, David | - |
dc.contributor.nonIdAuthor | Abramov, Andrey Y. | - |
dc.contributor.nonIdAuthor | Horrocks, Mathew H. | - |
dc.contributor.nonIdAuthor | Gandhi, Sonia | - |
dc.description.isOpenAccess | N | - |
dc.type.journalArticle | Article | - |
dc.subject.keywordPlus | PARKINSONS-DISEASE | - |
dc.subject.keywordPlus | STEM-CELLS | - |
dc.subject.keywordPlus | PROTEIN | - |
dc.subject.keywordPlus | OLIGOMERS | - |
dc.subject.keywordPlus | FLUORESCENCE | - |
dc.subject.keywordPlus | AGGREGATION | - |
dc.subject.keywordPlus | MICROSCOPY | - |
dc.subject.keywordPlus | FIBRILLIZATION | - |
dc.subject.keywordPlus | TRANSITION | - |
dc.subject.keywordPlus | INFLUX | - |
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