939. Viral Vector-Mediated Chaperone Gene Therapy in a Mouse Model of Sporadic Parkinson Disease

Abstract

Mitochondrial dysfunction and oxidative stress have been implicated in Parkinson's disease (PD). In addition, genetic evidence points to an important role of protein misfolding, aggregation and failure in the proteasomal degradation of specific neuronal proteins in the pathogenesis of PD. The chaperone heat shock protein 70 (Hsp-70) reduces protein misfolding and aggregation and protects cells against a variety of adverse conditions, including oxidative stress. Moreover, Hsp70 exerts anti-apoptotic activity by blocking the function of several key pro-apoptotic factors. Recently, Hsp70 was shown to inhibit alpha-synuclein toxicity in a Drosophila model of inherited PD. Here we tested the potential of Hsp70 for gene therapy in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of idiopathic PD. We show that Hsp70 gene transfer to dopamine neurons by a recombinant adeno-associated virus significantly protects the mouse dopaminergic system against MPTP-induced dopamine neuron loss and the associated decline in striatal dopamine levels and tyrosine hydroxylase-positive fibers. Hsp70 reduced MPTP-induced apoptosis in the substantia nigra, and unilateral protection of the dopaminergic system by Hsp70 was associated with increased amphetamine-induced turning towards the non-injected side. Collectively, these results suggest that increasing chaperone activity may be beneficial for the treatment of PD.