Modulation of neurodegeneration by molecular chaperones.
Many neurodegenerative disorders are characterized by conformational changes in proteins that result in misfolding, aggregation and intra- or extra-neuronal accumulation of amyloid fibrils. Molecular chaperones provide a first line of defence against misfolded, aggregation-prone proteins and are among the most potent suppressors of neurodegeneration known for animal models of human disease. Recent studies have investigated the role of molecular chaperones in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and polyglutamine diseases. We propose that molecular chaperones are neuroprotective because of their ability to modulate the earliest aberrant protein interactions that trigger pathogenic cascades. A detailed understanding of the molecular basis of chaperone-mediated protection against neurodegeneration might lead to the development of therapies for neurodegenerative disorders that are associated with protein misfolding and aggregation.
Muchowski
Paul J
PJ
Department of Pharmacology, The Center for Neurogenetics and Neurotherapeutics, University of Washington, Seattle, Washington 98195-7280, USA. mucho@u.washington.edu
Wacker
Jennifer L
JL
D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000378:metabolism
D018832:Molecular Chaperones; D018696:Neuroprotective Agents