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

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…

• MJ
  Michael J. Fox Foundation for Parkinson's Research

  Award: ASAP-000509
• W
  Wellcome

  Award: WT089698
• WT
  Wellcome Trust

  Awards: WT089698, CC0102, CC0199
• FC
  Francis Crick Institute

  Award: CC0199
• CR
  Cancer Research UK

  Awards: CC0102, CC0199
• PU
  Parkinson's UK
• SF
  Scottish Funding Council

  Awards: H14052, H14052/SIRL
• UC
  University College London
• RT
  Rosetrees Trust

  Award: WT089698
• AR
  Alzheimer’s Research UK

  Award: ARUK-EG2018B-004)
• GC
  Government Council on Grants, Russian Federation

  Award: 075-15-2019-1877
• UD
  UK Dementia Research Institute
• MR
  Medical Research Council

  Awards: CC0199, EP/L016559/1, WT089698, CC0102, MR/T008199/1, MR/T008199/1
• EA
  Engineering and Physical Sciences Research Council

  Award: EP/L016559/1
• BA
  Biotechnology and Biological Sciences Research Council

  Award: BB/S019707/1