Heat Shock Protein 70 Reduces alpha-Synuclein-Induced Predegenerative Neuronal Dystrophy in the alpha-Synuclein Viral Gene Transfer Rat Model of Parkinson's Disease

Research output: Contribution to journalArticle

Abstract

AimsIt has become increasingly evident that the nigrostriatal degeneration associated with Parkinson's disease initiates at the level of the axonal terminals in the putamen, and this nigrostriatal terminal dystrophy is either caused or exacerbated by the presence of -synuclein immunopositive neuronal inclusions. Therefore, strategies aimed at reducing -synuclein-induced early neuronal dystrophy may slow or halt the progression to overt nigrostriatal neurodegeneration. Thus, this study sought to determine if adeno-associated virus (AAV) mediated overexpression of two molecular chaperone heat shock proteins, namely Hsp27 or Hsp70, in the AAV--synuclein viral gene transfer rat model of Parkinson's disease could prevent -synuclein-induced early neuronal pathology. MethodsMale Sprague-Dawley rats were intranigrally coinjected with pathogenic (AAV--synuclein) and putative therapeutic (AAV-Hsp27 or AAV-Hsp70) viral vectors and were sacrificed 18weeks postviral injection. ResultsIntranigral injection of AAV--synuclein resulted in significant -synuclein accumulation in the substantia nigra and striatal terminals which led to significant dystrophy of nigrostriatal dopaminergic neurons without overt nigrostriatal neurodegeneration. Coinjection of AAV-Hsp70, but not AAV-Hsp27, significantly reduced AAV--synuclein-induced neuronal dystrophy. ConclusionsThese data confirm that overexpression of Hsp70 holds significant potential as a disease-modulating therapeutic approach for Parkinson's disease, with protective effects against early-onset -synuclein-induced pathology demonstrated in the AAV--synuclein model.

Details

Authors
  • Teresa C. Moloney
  • Rhona Hyland
  • Daniel O'Toole
  • Alexia Paucard
  • Deniz Kirik
  • Aideen O'Doherty
  • Adrienne M. Gorman
  • Eilis Dowd
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurosciences

Keywords

  • Genetic therapy, Heat-shock proteins, Parkinson's disease
Original languageEnglish
Pages (from-to)50-58
JournalCNS Neuroscience & Therapeutics
Volume20
Issue number1
Publication statusPublished - 2014
Publication categoryResearch
Peer-reviewedYes