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Molecular Chaperones as Rational Drug Targets for Parkinson's Disease Therapeutics

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Parkinson's 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 Parkinson's disease and of genetic susceptibility variants for idiopathic Parkinson's 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 Parkinson's 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 Parkinson's disease.





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Keywords: 1-deoxygalactonojirimycin; AADC; BAG Family Proteins; Bcl-2 associated athanogene (BAG) family; C-terminal Hsp70 interacting protein (CHIP); CAIR-1; Drosophila; Hip; Hsp70; Hsp90; Hsp90 inhibitors; Huntington's disease; JNK cell death pathway; LRRK2; PINK1; Parkinson's disease; SNpc; SODD; Scythe; allylamino)-17-demethoxygeldanamycin; alvespimycin; autophagy-lysosomal pathway; bradykinesia; chaperone complex; chaperones; co-chaperones; geldanamycin; heat shock cognates; heat shock protein; heat shock protein (Hsp); lysosomal pathways; neurodegeneration; protein (Hsp); protein homeostasis; proteostasis; radicicol; retaspimycin; spinocerebellar ataxias; tanespimycin; ubiquitin-proteasome system

Document Type: Research Article

Publication date: 2010-12-01

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  • CNS & Neurological Disorders - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in neurological and central nervous system (CNS) disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in neurological and CNS disorders. As the discovery, identification, characterization and validation of novel human drug targets for neurological and CNS drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.
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