( Researchers at the Burnham Institute fo...)Key stress protein linked to toxicities responsible for Parkinson's, Alzheimer's

Researchers at the Burnham Institute for Medical Research have discovered a mechanistic link between cellular stress caused by free radicals and accumulation of misfolded proteins that lead to nerve cell injury and death in neurodegenerative disorders such as Alzheimer's and Parkinson's Disease.

That link is Protein Disulphide Isomerase (PDI), a chaperone protein that is necessary for proper protein folding in times of cellular stress. Published in today's issue of Nature, these findings revealed that in patients with Alzheimer's and Parkinson's Disease, overproduction of free radicals, specifically nitric oxide (NO), causes inhibition of PDI by a reaction called S-nitrosylation, thereby reducing PDI's neuroprotective benefits. This data provides the first molecular link between NO free radicals and protein misfolding, which is currently thought to be a common pathway in the pathogenesis of virtually all neurodegenerative conditions. Such conditions also include ALS (or Lou Gehrig's disease), Huntington's disease, and many others. Understanding the PDI pathway may lead to the development of new therapeutic approaches for these neurodegenerative diseases and other disorders associated with abnormal protein accumulations due to cellular stress.

"To our knowledge, this is the first published evidence of a link between protein misfolding due to enzymatic machinery malfunction found in a number of degenerative diseases and free radical stress in nerve cells," said Stuart A. Lipton, M.D., Ph.D., Professor and Director of the Del E. Webb Center for Neurosciences and Aging at the Burnham Institute and senior author of the study. Dr. Lipton is also a clinical neurologist in La Jolla. "Our data demonstrate a previously unrecognized relationship between NO and protein misfolding in degenerative disorders, showing that PDI can be a target of NO in cellular models of Parkinson's disease and human neurodegenerative disease."

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Source:Burnham Institute

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