Journal
JOURNAL OF ALZHEIMERS DISEASE
Volume 60, Issue -, Pages S133-S150Publisher
IOS PRESS
DOI: 10.3233/JAD-170342
Keywords
Alpha-synuclein; iPSC-derived neural progenitor cells; iron; neurodegeneration; Parkinson's disease
Categories
Funding
- National Institutes of Health [USPHS R01 NS088 645]
- Muscular Dystrophy Association [MDA 294 842]
- Alzheimer's Association [NIRG-12-242135]
- Houston Methodist Research Institute
- Melo Brain Funds
- Institute for Training and Development of Human Resources of Panama (IFARHU)
- National Secretariat for Science, Technology, and Innovation of Panama (SENACYT)
- National System on Investigation grant of SENACYT
- USPHS [R01 GM105090]
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Alpha-synuclein (alpha-Syn) overexpression and misfolding/aggregation in degenerating dopaminergic neurons have long been implicated in Parkinson's disease (PD). The neurotoxicity of alpha-Syn is enhanced by iron (Fe) and other pro-oxidant metals, leading to generation of reactive oxygen species in PD brain. Although alpha-Syn is predominantly localized in presynaptic nerve terminals, a small fraction exists in neuronal nuclei. However, the functional and/or pathological role of nuclear alpha-Syn is unclear. Following up on our earlier report that alpha-Syn directly binds DNA in vitro, here we confirm the nuclear localization and chromatin association of alpha-Syn in neurons using proximity ligation and chromatin immunoprecipitation analysis. Moderate (similar to 2-fold) increase in alpha-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, alpha-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 alpha-Syn suggests that DNA nicking activity is mediated by the chemical nuclease activity of an oxidized peptide segment in the misfolded alpha-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, alpha-Syn combined with Fe significantly promoted neuronal cell death. Together, these findings provide a novel molecular insight into the direct role of alpha-Syn in inducing neuronal genome damage, which could possibly contribute to neurodegeneration in PD.
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