title: Chaperone-dependent Neurodegeneration: A Molecular Perspective on Therapeutic Intervention.
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.
authors.affiliation: Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Centre, New York, NY, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Carman
authors.affiliation: Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Centre, New York, NY, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kishinevsky
authors.affiliation: Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Centre, New York, NY, USA.
authors.forename: John
authors.initials: J
authors.lastname: Koren
authors.affiliation: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Lou
authors.affiliation: Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Centre, New York, NY, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Chiosis
keywords: Aberrant neurological proteins; Chaperone inhibitors; Molecular chaperones; Neurodegeneration