Free radical stress in nerve cells

ironjustice@aol.com · medicine forum Guru Joined: 28 Apr 2005 Posts: 1522

Contact: Nancy Beddingfield
nbeddingfield@burnham.org
858-646-3146
Burnham Institute

Key stress protein linked to toxicities responsible for Parkinson's,
Alzheimer's
Protein Disulphide Isomerase identified as marker for disease,
potential drug target
La Jolla, CA -- 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."

A protein's structure determines its function. Genetic defects as well
as exposure to free radicals or possibly other types of cellular stress
can cause small structural defects that lead to protein misfolding. If
the misfolded proteins cannot be refolded properly or degraded, they
may build up in the cell to cause dysfunction. Defects in either the
protein folding or degradation pathways can lead to accumulation of
misfolded proteins. The accumulation of misfolded proteins is a common
pathogenic mechanism in many diseases, including neurodegenerative
disorders.

In normal circumstances, PDI levels increase in response to
accumulation of misfolded proteins due to cellular stress. PDI acts as
a chaperone for aggregated proteins, rearranging their chemical bonds
and thus refolding the proteins to function normally. The new research
by Dr. Lipton and his colleagues shows that molecules related to the
free radical NO, which is present in elevated levels in
neurodegenerative diseases, attacks PDI via a chemical S-nitroyslation
reaction, altering PDI's structure and blocking its normal
neuroprotective function, which ultimately leads to nerve cell injury
and even death. These new results also show that this altered form of
PDI is present in elevated amounts in patients with Alzheimer's and
Parkinson's Disease, indicating that it is a potential marker for the
disease as well as a potential therapeutic target.

###
This article titled "S-Nitrosylated protein-disulphide isomerase links
protein misfolding to neurodegeneration," is authored by Drs. Takashi
Uehara, Tomohiro Nakamura, Dongdong Yao, Zhong-Qing Shi, and Zezong Gu
(all in Dr. Lipton's laboratory), Yuliang Ma (in the Protein Analysis
Facility at the Burnham), Eliezer Masliah (at UCSD), Yasuyuki Nomura
(at Hokkaido University in Sapporo, Japan), and Dr. Lipton, the senior
author. (Dr. Uehara recently joined the faculty of Hokkaido
University.)

This research was supported by grants from the National Institutes of
Health, the American Parkinson's Disease Association, San Diego
Chapter, an Ellison Senior Scholars Award in Aging, the Mitsubishi
Pharma Research Foundation, and a grant-in-aid from the Ministry of
Education, Culture, Sports and Technology of Japan.

About the Burnham Institute for Medical Research
The Burnham Institute for Medical Research, founded in 1976, is an
independent not-for-profit biomedical research institution dedicated to
advancing the frontiers of scientific knowledge and providing the
foundation for tomorrow's medical therapies. The Institute is home to
three major centers: the Cancer Center, the Del E. Webb Neuroscience
and Aging Center, and the Infectious and Inflammatory Disease Center.
Since 1981, the Institute's Cancer Center has been a member of the
National Cancer Institute's prestigious Cancer Centers program.
Discoveries by Burnham scientists have contributed to the development
of new drugs for Alzheimer's disease, heart disease and several forms
of cancer. Today the Institute employs over 725, including more than
550 scientists. The majority of the Institute's funding derives from
federal sources, but private philanthropic support is essential to
continuing bold and innovative research. For additional information
about the Institute and ways to support the research efforts of the
Institute, visit www.burnham.org.

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