Chaperone-dependent Neurodegeneration: A Molecular Perspective on Therapeutic Intervention

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.