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

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

Author information

1
Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX, USA.
2
Centre for Neuroscience, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología, City of Knowledge, Republic of Panama.
3
Department of Biotechnology, Acharya Nagarjuna University, Guntur, India.
4
Weill Cornell Medical College of Cornell University, NY, USA.
5
Houston Methodist Neurological Institute, Institute of Academic Medicine, Houston Methodist Hospital, Houston, TX, USA.

Abstract

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

PMID:
28731447
PMCID:
PMC6172953
DOI:
10.3233/JAD-170342
[Indexed for MEDLINE]
Free PMC Article

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