Identification of a highly neurotoxic α-synuclein species inducing mitochondrial damage and mitophagy in Parkinson's disease

Proc Natl Acad Sci U S A. 2018 Mar 13;115(11):E2634-E2643. doi: 10.1073/pnas.1713849115. Epub 2018 Feb 27.


Exposure of cultured primary neurons to preformed α-synuclein fibrils (PFFs) leads to the recruitment of endogenous α-synuclein and its templated conversion into fibrillar phosphorylated α-synuclein (pα-synF) aggregates resembling those involved in Parkinson's disease (PD) pathogenesis. Pα-synF was described previously as inclusions morphologically similar to Lewy bodies and Lewy neurites in PD patients. We discovered the existence of a conformationally distinct, nonfibrillar, phosphorylated α-syn species that we named "pα-syn*." We uniquely describe the existence of pα-syn* in PFF-seeded primary neurons, mice brains, and PD patients' brains. Through immunofluorescence and pharmacological manipulation we showed that pα-syn* results from incomplete autophagic degradation of pα-synF. Pα-synF was decorated with autophagic markers, but pα-syn* was not. Western blots revealed that pα-syn* was N- and C-terminally trimmed, resulting in a 12.5-kDa fragment and a SDS-resistant dimer. After lysosomal release, pα-syn* aggregates associated with mitochondria, inducing mitochondrial membrane depolarization, cytochrome C release, and mitochondrial fragmentation visualized by confocal and stimulated emission depletion nanoscopy. Pα-syn* recruited phosphorylated acetyl-CoA carboxylase 1 (ACC1) with which it remarkably colocalized. ACC1 phosphorylation indicates low ATP levels, AMPK activation, and oxidative stress and induces mitochondrial fragmentation via reduced lipoylation. Pα-syn* also colocalized with BiP, a master regulator of the unfolded protein response and a resident protein of mitochondria-associated endoplasmic reticulum membranes that are sites of mitochondrial fission and mitophagy. Pα-syn* aggregates were found in Parkin-positive mitophagic vacuoles and imaged by electron microscopy. Collectively, we showed that pα-syn* induces mitochondrial toxicity and fission, energetic stress, and mitophagy, implicating pα-syn* as a key neurotoxic α-syn species and a therapeutic target.

Keywords: Parkinson’s disease; alpha-synuclein; autophagy; mitochondria; toxicity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyl-CoA Carboxylase / chemistry
  • Acetyl-CoA Carboxylase / metabolism
  • Animals
  • Autophagy / drug effects*
  • Brain / drug effects
  • Brain / pathology
  • Brain Chemistry
  • Cell Culture Techniques
  • Cells, Cultured
  • Humans
  • Lysosomes / metabolism
  • Mice
  • Mitochondria
  • Mitophagy / drug effects*
  • Neurotoxins* / chemistry
  • Neurotoxins* / metabolism
  • Neurotoxins* / toxicity
  • Oxidative Stress / drug effects
  • Parkinson Disease / metabolism*
  • Phosphorylation
  • alpha-Synuclein* / chemistry
  • alpha-Synuclein* / metabolism
  • alpha-Synuclein* / toxicity


  • Neurotoxins
  • alpha-Synuclein
  • Acetyl-CoA Carboxylase