title: Heat shock protein 70 reduces α-synuclein-induced predegenerative neuronal dystrophy in the α-synuclein viral gene transfer rat model of Parkinson's disease.
abstract: OBJECTIVE
  It 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 α-synuclein immunopositive neuronal inclusions. Therefore, strategies aimed at reducing α-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-α-synuclein viral gene transfer rat model of Parkinson's disease could prevent α-synuclein-induced early neuronal pathology.
  
  
  METHODS
  Male Sprague-Dawley rats were intranigrally coinjected with pathogenic (AAV-α-synuclein) and putative therapeutic (AAV-Hsp27 or AAV-Hsp70) viral vectors and were sacrificed 18 weeks postviral injection.
  
  
  RESULTS
  Intranigral injection of AAV-α-synuclein resulted in significant α-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-α-synuclein-induced neuronal dystrophy.
  
  
  CONCLUSIONS
  These 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 α-synuclein-induced pathology demonstrated in the AAV-α-synuclein model.
authors.affiliation: Department of Pharmacology & Therapeutics, National University of Ireland, Galway, Ireland; National Centre for Biomedical Engineering Science (NCBES), National University of Ireland, Galway, Ireland; NCBES Galway Neuroscience Centre, National University of Ireland, Galway, Ireland.
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Moloney
authors.forename: Rhona
authors.initials: R
authors.lastname: Hyland
authors.forename: Daniel
authors.initials: D
authors.lastname: O'Toole
authors.forename: Alexia
authors.initials: A
authors.lastname: Paucard
authors.forename: Deniz
authors.initials: D
authors.lastname: Kirik
authors.forename: Aideen
authors.initials: A
authors.lastname: O'Doherty
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Gorman
authors.forename: Eilís
authors.initials: E
authors.lastname: Dowd
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009434:Neural Pathways / Q000378:metabolism / Q000473:pathology; D019150:Neuroaxonal Dystrophies / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018696:Neuroprotective Agents; C497604:SNCA protein, human; D051844:alpha-Synuclein
keywords: Genetic therapy; Heat-shock proteins; Parkinson's disease