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Synthetic alpha-synuclein fibrils cause mitochondrial impairment and selective dopamine neurodegeneration in part via iNOS-mediated nitric oxide production.

TitleSynthetic alpha-synuclein fibrils cause mitochondrial impairment and selective dopamine neurodegeneration in part via iNOS-mediated nitric oxide production.
Publication TypeJournal Article
Year of Publication2017
AuthorsTapias V, Hu X, Luk KC, Sanders LH, Lee VM, J Greenamyre T
JournalCell Mol Life Sci
Volume74
Issue15
Pagination2851-2874
Date Published2017 08
ISSN1420-9071
Keywordsalpha-Synuclein, Animals, Cell Survival, Cells, Cultured, Dopaminergic Neurons, Humans, Inflammation, Mesencephalon, Mitochondria, Nitric Oxide, Nitric Oxide Synthase Type II, Oxidative Stress, Parkinson Disease, Protein Aggregation, Pathological, Rats, Sprague-Dawley
Abstract

Intracellular accumulation of α-synuclein (α-syn) are hallmarks of synucleinopathies, including Parkinson's disease (PD). Exogenous addition of preformed α-syn fibrils (PFFs) into primary hippocampal neurons induced α-syn aggregation and accumulation. Likewise, intrastriatal inoculation of PFFs into mice and non-human primates generates Lewy bodies and Lewy neurites associated with PD-like neurodegeneration. Herein, we investigate the putative effects of synthetic human PFFs on cultured rat ventral midbrain dopamine (DA) neurons. A time- and dose-dependent accumulation of α-syn was observed following PFFs exposure that also underwent phosphorylation at serine 129. PFFs treatment decreased the expression levels of synaptic proteins, caused alterations in axonal transport-related proteins, and increased H2AX Ser139 phosphorylation. Mitochondrial impairment (including modulation of mitochondrial dynamics-associated protein content), enhanced oxidative stress, and an inflammatory response were also detected in our experimental paradigm. In attempt to unravel a potential molecular mechanism of PFFs neurotoxicity, the expression of inducible nitric oxide synthase was blocked; a significant decline in protein nitration levels and protection against PFFs-induced DA neuron death were observed. Combined exposure to PFFs and rotenone resulted in an additive toxicity. Strikingly, many of the harmful effects found were more prominent in DA rather than non-DA neurons, suggestive of higher susceptibility to degenerate. These findings provide new insights into the role of α-syn in the pathogenesis of PD and could represent a novel and valuable model to study DA-related neurodegeneration.

DOI10.1007/s00018-017-2541-x
Alternate JournalCell. Mol. Life Sci.
PubMed ID28534083
PubMed Central IDPMC5524146
Grant ListR01 NS095387 / NS / NINDS NIH HHS / United States