Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity.

Autor:	Choi ML; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.; The Francis Crick Institute, London, UK.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA., Chappard A; EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, UK., Singh BP; EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, UK.; School of Physics, University of Edinburgh, Edinburgh, UK., Maclachlan C; The Francis Crick Institute, London, UK., Rodrigues M; Department of Chemistry, University of Cambridge, Cambridge, UK.; Dementia Research institute at University of Cambridge, Cambridge, UK., Fedotova EI; Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Russia.; Cell Physiology and Pathology Laboratory, Orel State University, Orel, Russia., Berezhnov AV; Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Russia.; Cell Physiology and Pathology Laboratory, Orel State University, Orel, Russia., De S; Department of Chemistry, University of Cambridge, Cambridge, UK.; Dementia Research institute at University of Cambridge, Cambridge, UK., Peddie CJ; The Francis Crick Institute, London, UK., Athauda D; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.; The Francis Crick Institute, London, UK., Virdi GS; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.; The Francis Crick Institute, London, UK.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA., Zhang W; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.; The Francis Crick Institute, London, UK., Evans JR; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.; The Francis Crick Institute, London, UK.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA., Wernick AI; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.; The Francis Crick Institute, London, UK.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA., Zanjani ZS; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.; The Francis Crick Institute, London, UK.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA., Angelova PR; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK., Esteras N; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK., Vinokurov AY; Cell Physiology and Pathology Laboratory, Orel State University, Orel, Russia., Morris K; EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, UK., Jeacock K; EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, UK., Tosatto L; Department of Chemistry, University of Cambridge, Cambridge, UK.; Istituto di Biofisica, National Council of Research, Trento, Italy., Little D; MRC Laboratory for Molecular Cell Biology, University College London, London, UK.; NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK., Gissen P; MRC Laboratory for Molecular Cell Biology, University College London, London, UK.; NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK., Clarke DJ; EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, UK., Kunath T; Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh, UK., Collinson L; The Francis Crick Institute, London, UK., Klenerman D; Department of Chemistry, University of Cambridge, Cambridge, UK.; Dementia Research institute at University of Cambridge, Cambridge, UK., Abramov AY; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. a.abramov@ucl.ac.uk.; Cell Physiology and Pathology Laboratory, Orel State University, Orel, Russia. a.abramov@ucl.ac.uk., Horrocks MH; EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, UK. mathew.horrocks@ed.ac.uk., Gandhi S; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. sonia.gandhi@ucl.ac.uk.; The Francis Crick Institute, London, UK. sonia.gandhi@ucl.ac.uk.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA. sonia.gandhi@ucl.ac.uk.
Jazyk:	angličtina
Zdroj:	Nature neuroscience [Nat Neurosci] 2022 Sep; Vol. 25 (9), pp. 1134-1148. Date of Electronic Publication: 2022 Aug 30.
DOI:	10.1038/s41593-022-01140-3
Abstrakt:	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. (© 2022. The Author(s).)
Databáze:	MEDLINE
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