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

Moloney, Teresa C.; Hyland, Rhona; O'Toole, Daniel; Paucard, Alexia; Kirik, Deniz LU ; O'Doherty, Aideen; Gorman, Adrienne M. and Dowd, Eilis (2014) In CNS Neuroscience & Therapeutics 20(1). p.50-58
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Genetic therapy, Heat-shock proteins, Parkinson's disease
in
CNS Neuroscience & Therapeutics
volume
20
issue
1
pages
50 - 58
publisher
Wiley-Blackwell
external identifiers
  • wos:000328572400007
  • scopus:84890506871
ISSN
1755-5949
DOI
10.1111/cns.12200
language
English
LU publication?
yes
id
1acbd745-0062-4c50-8007-dcb1271af894 (old id 4261865)
date added to LUP
2014-02-10 12:16:11
date last changed
2017-10-01 03:24:56
@article{1acbd745-0062-4c50-8007-dcb1271af894,
  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.},
  author       = {Moloney, Teresa C. and Hyland, Rhona and O'Toole, Daniel and Paucard, Alexia and Kirik, Deniz and O'Doherty, Aideen and Gorman, Adrienne M. and Dowd, Eilis},
  issn         = {1755-5949},
  keyword      = {Genetic therapy,Heat-shock proteins,Parkinson's disease},
  language     = {eng},
  number       = {1},
  pages        = {50--58},
  publisher    = {Wiley-Blackwell},
  series       = {CNS Neuroscience & Therapeutics},
  title        = {Heat Shock Protein 70 Reduces alpha-Synuclein-Induced Predegenerative Neuronal Dystrophy in the alpha-Synuclein Viral Gene Transfer Rat Model of Parkinson's Disease},
  url          = {http://dx.doi.org/10.1111/cns.12200},
  volume       = {20},
  year         = {2014},
}