Chromatin-Bound Oxidized α-Synuclein Causes Strand Breaks in Neuronal Genomes in in vitro Models of Parkinson’s Disease
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Alpha-synuclein (α-Syn) overexpression and misfolding/aggregation in degenerating dopaminergic neurons have long been implicated in Parkinson's disease (PD). The neurotoxicity of α-Syn is enhanced by iron (Fe) and other pro-oxidant metals, leading to generation of reactive oxygen species in PD brain. Although α-Syn is predominantly localized in presynaptic nerve terminals, a small fraction exists in neuronal nuclei. However, the functional and/or pathological role of nuclear α-Syn is unclear. Following up on our earlier report that α-Syn directly binds DNA in vitro, here we confirm the nuclear localization and chromatin association of α-Syn in neurons using proximity ligation and chromatin immunoprecipitation analysis. Moderate (∼2-fold) increase in α-Syn expression in neural lineage progenitor cells (NPC) derived from induced pluripotent human stem cells (iPSCs) or differentiated SHSY-5Y cells caused DNA strand breaks in the nuclear genome, which was further enhanced synergistically by Fe salts. Furthermore, α-Syn required nuclear localization for inducing genome damage as revealed by the effect of nucleus versus cytosol-specific mutants. Enhanced DNA damage by oxidized and misfolded/oligomeric α-Syn suggests that DNA nicking activity is mediated by the chemical nuclease activity of an oxidized peptide segment in the misfolded α-Syn. Consistent with this finding, a marked increase in Fe-dependent DNA breaks was observed in NPCs from a PD patient-derived iPSC line harboring triplication of the SNCA gene. Finally, α-Syn combined with Fe significantly promoted neuronal cell death. Together, these findings provide a novel molecular insight into the direct role of α-Syn in inducing neuronal genome damage, which could possibly contribute to neurodegeneration in PD.
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Toxic aggregation of α-synuclein in the nucleus or cytosol elicits the accumulation of DSBs.
“However, toxic aggregation of α‐synuclein in the nucleus or cytosol elicits the accumulation of DSBs (Vasquez et al, 2017; Milanese et al, 2018).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Vasquez et al, 2017
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Biological Amyloids Chemically Damage DNA
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- Authors
- Vasquez, V., Mitra, J., Hegde, P. M., Pandey, A., Sengupta, S., Mitra, S., Rao, K. S., & Hegde, M. L.
- Affiliations
- Houston Methodist (US)
- Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (PA)
- Corresponding author
- Rao, K.S.
- Hegde, Muralidhar L.
- ORCID
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2017-09-15
- Volume
- 60
- Issue
- s1
- Pages
- S133-S150
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- PMC
- PMC6172953
- OpenAlex
- W2739097448
- Cited by
- 88
- References
- 64
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 10 · 2023: 7 · 2022: 16 · 2021: 17 · 2020: 12 · 2019: 5 · 2018: 7 · 2016: 1
- FWCI
- 4.57
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM105090)
- National Institute of Neurological Disorders and Stroke (R01NS088645)
- 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, Parkinson's disease
- MeSH terms
- Cell Nucleolus, Chromatin, DNA Damage, Gene Expression Regulation, Humans, Iron, Neuroblastoma, Neurons, Oxidation-Reduction, Protein Binding, Sulfides, Cell Death, Annexin A5, Reactive Oxygen Species, Copper Sulfate, Comet Assay, Cell Line, Tumor, alpha-Synuclein, DNA Breaks, Double-Stranded, Neural Stem Cells, Nestin
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