Review Article
Chaperone-dependent Neurodegeneration: A Molecular Perspective on Therapeutic Intervention
Aaron Carman1, Sarah Kishinevsky1, John Koren III1, Wenjie Lou2 and Gabriela Chiosis1*
1Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Centre, New York, NY, USA
2Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY, USA
- Corresponding Author:
- Gabriela Chiosis
Department of Molecular Pharmacology and Chemistry
Memorial Sloan-Kettering Cancer Centre, New York, NY, USA
E-mail: chiosisg@MSKCC.ORG
Received date: March 22, 2013; Accepted date: April 08, 2013; Published date: April 24, 2013
Citation: Carman A, Kishinevsky S, John Koren III, Lou W, Chiosis G (2013) Chaperone-dependent Neurodegeneration: A Molecular Perspective on Therapeutic Intervention. J Alzheimers Dis Parkinsonism S10:007. doi:10.4172/2161-0460.S10-007
Copyright: © 2013 Carman A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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 polyQexpanded 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.
