Title: Molecular Chaperones as Rational Drug Targets for Parkinsons Disease Therapeutics
Volume: 9
Issue: 6
Author(s): S. K. Kalia, L. V. Kalia and P. J. McLean
Affiliation:
Keywords:
Bcl-2 associated athanogene (BAG) family, C-terminal Hsp70 interacting protein (CHIP), chaperones, co-chaperones, heat shock protein (Hsp), Hsp90 inhibitors, neurodegeneration, Parkinson's disease, ubiquitin-proteasome system, autophagy-lysosomal pathway, protein (Hsp), bradykinesia, SNpc, protein homeostasis, PINK1, Drosophila, heat shock protein, heat shock cognates, Hsp70, chaperone complex, spinocerebellar ataxias, JNK cell death pathway, proteostasis, BAG Family Proteins, CAIR-1, SODD, Scythe, lysosomal pathways, LRRK2, Hip, Hsp90, allylamino)-17-demethoxygeldanamycin, tanespimycin, alvespimycin, geldanamycin, radicicol, retaspimycin, AADC, Huntington's disease, 1-deoxygalactonojirimycin
Abstract: Parkinsons disease is a neurodegenerative movement disorder that is caused, in part, by the loss of dopaminergic neurons within the substantia nigra pars compacta of the basal ganglia. The presence of intracellular protein aggregates, known as Lewy bodies and Lewy neurites, within the surviving nigral neurons is the defining neuropathological feature of the disease. Accordingly, the identification of specific genes mutated in families with Parkinsons disease and of genetic susceptibility variants for idiopathic Parkinsons disease has implicated abnormalities in proteostasis, or the handling and elimination of misfolded proteins, in the pathogenesis of this neurodegenerative disorder. Protein folding and the refolding of misfolded proteins are regulated by a network of interactive molecules, known as the chaperone system, which is composed of molecular chaperones and co-chaperones. The chaperone system is intimately associated with the ubiquitin-proteasome system and the autophagy-lysosomal pathway which are responsible for elimination of misfolded proteins and protein quality control. In addition to their role in proteostasis, some chaperone molecules are involved in the regulation of cell death pathways. Here we review the role of the molecular chaperones Hsp70 and Hsp90, and the cochaperones Hsp40, BAG family members such as BAG5, CHIP and Hip in modulating neuronal death with a focus on dopaminergic neurodegeneration in Parkinsons disease. We also review current progress in preclinical studies aimed at targetting the chaperone system to prevent neurodegeneration. Finally, we discuss potential future chaperone-based therapeutics for the symptomatic treatment and possible disease modification of Parkinsons disease.
