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Reactions to Protein Stress in Neurodegenerative Disease – Sometimes Good, Sometimes Bad and Always Ugly

For release: Friday, March 14, 2008

If you could look inside the dying brain cells of someone with Alzheimer's disease or a variety of lesser-known neurodegenerative diseases, you would see gobs of misshapen proteins.  Research has shown that cells have a cleanup system for handling this protein "stress," and some studies suggest the possibility of developing therapeutic drugs that would work by giving the system a boost. 

But a new study published in Neuron* suggests that during prolonged stress, the cleanup system can suppress vital cell functions or even actively kill the cell.  A team led by Lawrence Wrabetz, M.D., of the San Raffaele Scientific Institute in Milan, Italy found that eliminating part of the cleanup system improved pathology in a mouse model of Charcot-Marie-Tooth disease (CMT).  The work was supported in part by the National Institute of Neurological Disorders and Stroke (NINDS).

“Over the years, Dr. Wrabetz has made seminal discoveries in understanding the pathogenesis of CMT, and has helped other scientists in the CMT field by sharing his resources and expertise," says John Porter, Ph.D., a program director at NINDS.  "These latest findings point toward potential therapeutic avenues that may have impact for neurological disorders well beyond CMT.”

Specifically, the findings suggest that scientists still have much to learn about cellular reactions to abnormal proteins and how to harness those reactions for therapeutic purposes.

CMT is a relatively rare genetic disease characterized by progressive nerve damage.  The genetic cause of the disease varies in different families.  In fact, CMT has been linked to mutations in nearly 30 genes.  The most common mutations lead to an erosion of myelin – a protective sheath that surrounds nerve fibers.

Dr. Wrabetz and his colleagues studied mice with a mutation affecting P0, a protein normally found in peripheral nerve myelin, where it is produced by cells called Schwann cells.  The mutation (S63del) causes the P0 protein to adopt an abnormal, misfolded shape and become trapped within the inner recesses of Schwann cells.

This kind of protein accumulation is toxic to cells, and triggers a survival mechanism known as the unfolded protein response (UPR).  The UPR typically directs abnormal proteins to the proteasome, a barrel-shaped structure that acts like a protein garbage disposal.  It also might shuttle them to lysosomes, tiny packets filled with acids and protein-cutting enzymes.  In laboratory models of Alzheimer's, Parkinson's, Huntington's and other diseases, interfering with lysosome or proteasome activity hastens neuronal death.

In their study, Dr. Wrabetz and his colleagues focused on CHOP – a protein that helps drive the UPR – and its role in the S63del mouse model of CMT.  They expected that the mutant P0 protein would trigger CHOP activity, and that CHOP would protect against the protein's toxicity.  Indeed, CHOP activity was elevated in the mice.  But surprisingly, knocking out the CHOP gene ameliorated overt signs of the disease.  It also reduced the loss of myelin and improved Schwann cell survival.

The reasons for the result aren't clear.  But there is evidence that when a cell is overrun by misfolded proteins and beyond repair, CHOP activates a program of cell suicide, Dr. Wrabetz says.  He also points out that CHOP activity doesn't just reduce protein "stress" by clearing away misfolded proteins; it puts a temporary hold on all protein manufacture.  So, in S63del mice, elevated CHOP activity could prevent Schwann cells from making essential components of myelin.

Overall, the results show that "it's too simplistic" to label the UPR as either "adaptive or maladaptive," Dr. Wrabetz says.  It could shield cells against protein stress, it could act as a self-destruct switch or, by suppressing protein production, it could cause cell function to run down.  The nature of the response probably depends on the identity of the misfolded protein, the stage of disease, the affected cell type and other factors.  Scientists will have to confront these issues as they move toward developing drugs that target the UPR, he says.

NINDS is a component of the National Institutes of Health (NIH) within the Department of Health and Human Services.  The NIH — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research. It investigates the causes, treatments, and cures for both common and rare diseases.  For more information about NIH and its programs, visit

-By Daniel Stimson, Ph.D.

*Pennuto M et al.  "Ablation of the UPR-Mediator CHOP Restores Motor Function and Reduces Demyelination in Charcot-Marie-Tooth 1B Mice."  Neuron, February 7, 2008, Vol. 57, pp. 393-405.

Last Modified March 21, 2008