Journal
NATURE NEUROSCIENCE
Volume 25, Issue 9, Pages 1134-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41593-022-01140-3
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Funding
- Wellcome/Medical Research Council (MRC) Parkinson's Disease Consortium grant [WT089698]
- National Institute of Health Research University College London Hospitals Biomedical Research Centre
- Wellcome [100172/Z/12/2]
- Aligning Science Across Parkinson's
- Michael J. Fox Foundation
- MRC [MR/T008199/1]
- Russian Federation Government [075-15-2019-1877]
- Francis Crick Institute from Cancer Research UK [CC0102, CC0199]
- UK Medical Research Council [CC0102, CC0199]
- Wellcome Trust [CC0102, CC0199]
- UK Dementia Research Institute
- UCB Biopharmaceuticals
- Alzheimer's Research UK [ARUK-EG2018B-004]
- Engineering and Physical Sciences Research Council
- MRC through the Centre for Doctoral Training in Optical Medical Imaging [EP/L016559/1]
- Rosetrees Trust
- Scottish Funding Council [H14052/SIRL ID: 691]
- BBSRCEastBIO doctoral training programme [BB/M010996/1]
- Parkinson's UK Senior Fellowship
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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.
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.
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