Identification Of A Highly Neurotoxic Alpha-Synuclein Species Inducing Mitochondrial Damage And Mitophagy In Parkinson'S Disease
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA(2018)
摘要
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 (p alpha-synF) aggregates resembling those involved in Parkinson's disease (PD) pathogenesis. P alpha-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 "p alpha-syn*." We uniquely describe the existence of p alpha-syn* in PFF-seeded primary neurons, mice brains, and PD patients' brains. Through immunofluorescence and pharmacological manipulation we showed that p alpha-syn* results from incomplete autophagic degradation of p alpha-synF. P alpha-synF was decorated with autophagic markers, but p alpha-syn* was not. Western blots revealed that p alpha-syn* was N- and C-terminally trimmed, resulting in a 12.5-kDa fragment and a SDS-resistant dimer. After lysosomal release, p alpha-syn* aggregates associated with mitochondria, inducing mitochondrial membrane depolarization, cytochrome C release, and mitochondrial fragmentation visualized by confocal and stimulated emission depletion nanoscopy. P alpha-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. P alpha-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. P alpha-syn* aggregates were found in Parkin-positive mitophagic vacuoles and imaged by electron microscopy. Collectively, we showed that p alpha-syn* induces mitochondrial toxicity and fission, energetic stress, and mitophagy, implicating p alpha-syn* as a key neurotoxic alpha-syn species and a therapeutic target.
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关键词
Parkinson's disease, mitochondria, toxicity, alpha-synuclein, autophagy
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