• English
    • español
  • English 
    • English
    • español
  • Login
View Item 
  •   DSpace Home
  • Investigación
  • Artículos Científicos
  • View Item
  •   DSpace Home
  • Investigación
  • Artículos Científicos
  • View Item
JavaScript is disabled for your browser. Some features of this site may not work without it.

Chromatin-bound oxidized α-synuclein causes strand breaks in neuronal genomes in in vitro models of Parkinson's Disease

Thumbnail
View/Open
Artículo Principal (2.837Mb)
Date
2019-09-01
Author
Vasquez, Velmarini
Mitra, Joy
Hegde, Pavana M
Pandey, Arvind
Sengupta, Shiladitya
Mitra, Sankar
Rao, KS Jagannatha
Hegde, Muralidhar L
Metadata
Show full item record
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.
URI
http://repositorio-indicasat.org.pa/handle/123456789/68
Collections
  • Artículos Científicos

El enlace del OAI de este repositorio: www.repositorio-indicasat.org.pa/oai/request
Repositorio del Instituto de Investigaciones Científicas y Servicios de Alta Tecnología de Panamá (INDICASAT).
Utiliza DSpace copyright © 2002-2016  DuraSpace
Contact Us | Send Feedback

 

 

Browse

All of DSpaceCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects

My Account

LoginRegister

Statistics

View Usage Statistics

El enlace del OAI de este repositorio: www.repositorio-indicasat.org.pa/oai/request
Repositorio del Instituto de Investigaciones Científicas y Servicios de Alta Tecnología de Panamá (INDICASAT).
Utiliza DSpace copyright © 2002-2016  DuraSpace
Contact Us | Send Feedback