Chromatin-Bound Oxidized α-Synuclein Causes Strand Breaks in Neuronal Genomes in in vitro Models of Parkinson's Disease

J Alzheimers Dis. 2017;60(s1):S133-S150. doi: 10.3233/JAD-170342.


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.

Keywords: Alpha-synuclein; Parkinson’s disease; iPSC-derived neural progenitor cells; iron; neurodegeneration.

MeSH terms

  • Annexin A5 / metabolism
  • Cell Death / physiology
  • Cell Line, Tumor
  • Cell Nucleolus / metabolism
  • Chromatin / metabolism*
  • Comet Assay
  • Copper Sulfate / pharmacology
  • DNA Breaks, Double-Stranded* / drug effects
  • DNA Damage / drug effects
  • DNA Damage / physiology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Humans
  • Iron / pharmacology
  • Nestin / metabolism
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism*
  • Neuroblastoma / pathology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Oxidation-Reduction / drug effects
  • Protein Binding / drug effects
  • Reactive Oxygen Species / metabolism
  • Sulfides / pharmacology
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*


  • Annexin A5
  • Chromatin
  • Nestin
  • Reactive Oxygen Species
  • Sulfides
  • alpha-Synuclein
  • greigite
  • Iron
  • Copper Sulfate