| First Author | Grassi D | Year | 2018 |
| Journal | Proc Natl Acad Sci U S A | Volume | 115 |
| Issue | 11 | Pages | E2634-E2643 |
| PubMed ID | 29487216 | Mgi Jnum | J:259769 |
| Mgi Id | MGI:6144182 | Doi | 10.1073/pnas.1713849115 |
| Citation | Grassi D, et al. (2018) Identification of a highly neurotoxic alpha-synuclein species inducing mitochondrial damage and mitophagy in Parkinson's disease. Proc Natl Acad Sci U S A 115(11):E2634-E2643 |
| abstractText | Exposure of cultured primary neurons to preformed alpha-synuclein fibrils (PFFs) leads to the recruitment of endogenous alpha-synuclein and its templated conversion into fibrillar phosphorylated alpha-synuclein (palpha-synF) aggregates resembling those involved in Parkinson''s disease (PD) pathogenesis. Palpha-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 alpha-syn species that we named "palpha-syn*." We uniquely describe the existence of palpha-syn* in PFF-seeded primary neurons, mice brains, and PD patients'' brains. Through immunofluorescence and pharmacological manipulation we showed that palpha-syn* results from incomplete autophagic degradation of palpha-synF. Palpha-synF was decorated with autophagic markers, but palpha-syn* was not. Western blots revealed that palpha-syn* was N- and C-terminally trimmed, resulting in a 12.5-kDa fragment and a SDS-resistant dimer. After lysosomal release, palpha-syn* aggregates associated with mitochondria, inducing mitochondrial membrane depolarization, cytochrome C release, and mitochondrial fragmentation visualized by confocal and stimulated emission depletion nanoscopy. Palpha-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. Palpha-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. Palpha-syn* aggregates were found in Parkin-positive mitophagic vacuoles and imaged by electron microscopy. Collectively, we showed that palpha-syn* induces mitochondrial toxicity and fission, energetic stress, and mitophagy, implicating palpha-syn* as a key neurotoxic alpha-syn species and a therapeutic target. |
