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

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Tapias, Victor, Hu, Xiaoping, Luk, Kelvin C., Sanders, Laurie H., Lee, Virginia M., Greenamyre, J. Timothy·2017·Cellular and Molecular Life Sciences
DOI 10.1007/s00018-017-2541-xPMC PMC5524146
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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.

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  • iNOS expression is enhanced in multiple PD animal models induced by 6-OHDA, MPTP, and aSyn oligomers.

    “In addition, iNOS expression was also found to be enhanced in multiple PD animal models induced by 6-OHDA,461 MPTP,462 and aSyn oligomers.463”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [463]

    The Results section (“Inflammatory response to alpha-synuclein fibril exposure”; page unavailable) reports increased iNOS in dopamine neurons exposed to α-synuclein preformed fibrils. The cited paper describes this as an in vitro model, not an animal model induced by α-synuclein oligomers. Citation 463 attaches to the α-synuclein part of the sentence, not the separately cited 6-OHDA and MPTP claims. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Tapias, V., Hu, X., Luk, K. C., Sanders, L. H., Lee, V. M., & Greenamyre, J. T.
Affiliations
  • University of Pittsburgh (US)
  • University of Pennsylvania (US)
ORCID
Venue
Cellular and Molecular Life Sciences
Publisher
Springer Science and Business Media LLC
Published
2017-05-22
Volume
74
Issue
15
Pages
2851-2874
ISSN
  • 1420-682X (ISSN-L)
  • 1420-9071
DOI
10.1007/s00018-017-2541-x
PMC
PMC5524146
OpenAlex
W2618767189
Cited by
126
References
6
Citations by year
2026: 13 · 2025: 16 · 2024: 4 · 2023: 13 · 2022: 16 · 2021: 17 · 2020: 21 · 2019: 10 · 2018: 11 · 2017: 5
FWCI
8.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Cellular and Molecular Life Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • UVaDOC UVaDOC University of Valladolid Documentary Repository (University of Valladolid) (submittedVersion, cc-by)
  • Hispana (submittedVersion, cc-by)
Funders
  • DSF Charitable Foundation
  • Consolidated Anti-Aging Foundation
  • National Institutes of Health (NS059806, NS095387, ES020718, ES020327)
  • Blechman Foundation
  • American Parkinson Disease Association
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
alpha-synuclein fibrils, Parkinson's disease, dopaminergic neurons, neurodegeneration, inducible nitric oxide synthase, nitric oxide, mitochondrial dysfunction, oxidative stress, protein nitration, rotenone, synucleinopathies, Lewy bodies, alpha-synuclein phosphorylation, axonal transport, neuroinflammation, ventral midbrain
MeSH terms
Animals, Cell Survival, Cells, Cultured, Humans, Inflammation, Mesencephalon, Mitochondria, Nitric Oxide, Parkinson Disease, Rats, Sprague-Dawley, Oxidative Stress, alpha-Synuclein, Nitric Oxide Synthase Type II, Dopaminergic Neurons, Protein Aggregation, Pathological

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