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

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. 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 18weeks postviral injection. 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. 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.