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Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity.
Choi, Minee L; Chappard, Alexandre; Singh, Bhanu P; Maclachlan, Catherine; Rodrigues, Margarida; Fedotova, Evgeniya I; Berezhnov, Alexey V; De, Suman; Peddie, Christopher J; Athauda, Dilan; Virdi, Gurvir S; Zhang, Weijia; Evans, James R; Wernick, Anna I; Zanjani, Zeinab Shadman; Angelova, Plamena R; Esteras, Noemi; Vinokurov, Andrey Y; Morris, Katie; Jeacock, Kiani; Tosatto, Laura; Little, Daniel; Gissen, Paul; Clarke, David J; Kunath, Tilo; Collinson, Lucy; Klenerman, David; Abramov, Andrey Y; Horrocks, Mathew H; Gandhi, Sonia.
Afiliação
  • Choi ML; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
  • Chappard A; The Francis Crick Institute, London, UK.
  • Singh BP; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
  • Maclachlan C; EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, UK.
  • Rodrigues M; EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, UK.
  • Fedotova EI; School of Physics, University of Edinburgh, Edinburgh, UK.
  • Berezhnov AV; The Francis Crick Institute, London, UK.
  • De S; Department of Chemistry, University of Cambridge, Cambridge, UK.
  • Peddie CJ; Dementia Research institute at University of Cambridge, Cambridge, UK.
  • Athauda D; Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Russia.
  • Virdi GS; Cell Physiology and Pathology Laboratory, Orel State University, Orel, Russia.
  • Zhang W; Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Russia.
  • Evans JR; Cell Physiology and Pathology Laboratory, Orel State University, Orel, Russia.
  • Wernick AI; Department of Chemistry, University of Cambridge, Cambridge, UK.
  • Zanjani ZS; Dementia Research institute at University of Cambridge, Cambridge, UK.
  • Angelova PR; The Francis Crick Institute, London, UK.
  • Esteras N; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
  • Vinokurov AY; The Francis Crick Institute, London, UK.
  • Morris K; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
  • Jeacock K; The Francis Crick Institute, London, UK.
  • Tosatto L; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
  • Little D; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
  • Gissen P; The Francis Crick Institute, London, UK.
  • Clarke DJ; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
  • Kunath T; The Francis Crick Institute, London, UK.
  • Collinson L; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
  • Klenerman D; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
  • Abramov AY; The Francis Crick Institute, London, UK.
  • Horrocks MH; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
  • Gandhi S; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
Nat Neurosci ; 25(9): 1134-1148, 2022 09.
Article em En | MEDLINE | ID: mdl-36042314
Aggregation of alpha-synuclein (α-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 α-Syn using a single-molecule Förster resonance energy transfer (smFRET) biosensor, and we show here that α-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 α-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 α-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 α-Syn oligomerization at mitochondrial membranes and subsequent neuronal toxicity.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Parkinson / Alfa-Sinucleína Limite: Humans Idioma: En Revista: Nat Neurosci Assunto da revista: NEUROLOGIA Ano de publicação: 2022 Tipo de documento: Article
Texto completo
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Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Parkinson / Alfa-Sinucleína Limite: Humans Idioma: En Revista: Nat Neurosci Assunto da revista: NEUROLOGIA Ano de publicação: 2022 Tipo de documento: Article