Abstract
Maintenance of cellular homeostasis is regulated by the molecular chaperones. Under pathogenic conditions, aberrant proteins are triaged by the chaperone network. These aberrant proteins, known as “clients,” have major roles in the pathogenesis of numerous neurological disorders, including tau in Alzheimer’s disease, α-synuclein and LRRK2 in Parkinson’s disease, SOD-1, TDP-43 and FUS in amyotrophic lateral sclerosis, and polyQ-expanded proteins such as huntingtin in Huntington’s disease. Recent work has demonstrated that the use of chemical compounds which inhibit the activity of molecular chaperones subsequently alter the fate of aberrant clients. Inhibition of Hsp90 and Hsc70, two major molecular chaperones, has led to a greater understanding of how chaperone triage decisions are made and how perturbing the chaperone system can promote clearance of these pathogenic clients. Described here are major pathways and components of several prominent neurological disorders. Also discussed is how treatment with chaperone inhibitors, predominately Hsp90 inhibitors which are selective for a diseased state, can relieve the burden of aberrant client signaling in these neurological disorders.
Highlights
Chaperones in disease Eukaryotes have evolved elaborate systems of chaperone proteins to cope with cellular stress
Similar to aberrant proteins in other neurodegenerative diseases, mutant SOD1 is a client of the Hsp70/heat-shock protein 90 (Hsp90) chaperone network [167], and its proteasomal degradation is largely regulated by the ubiquitin ligase CHIP [167,168,169]
Experimental evidence shows that Hsp70 binding results in aberrant client degradation, most likely by increasing the possibility that the Hsp70-client complex will be ubiquitinated by CHIP and eventually degraded
Summary
Chaperones in disease Eukaryotes have evolved elaborate systems of chaperone proteins to cope with cellular stress. Does Hsp90 inhibition decrease levels of tau phosphorylated on Ser202, a pathogenically-important site known to be phosphorylated by Cdk5, and levels of the Cdk5-activator protein p35, which is itself a client of the Hsp90 chaperone network. Hsp70 inhibition reduced tau levels in cell-based models, perhaps by locking client tau and Hsp70 together, resulting in their ubiquitination and degradation [99].
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