The ALS Association

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Carrie Munk
The ALS Association
(571) 319-3047



ALS Protein Risks Misfolding to Do Its Normal Function

Washington, D.C. (February 21, 2013)—In work supported by The ALS Association, researchers have shown that a prominent ALS-related protein may misfold as a result of its normal function, an insight that may help tailor therapies designed to prevent misfolding. The study was published in the Journal of Biological Chemistry.

ALS (amyotrophic lateral sclerosis), often referred to as Lou Gehrig’s Disease, is a progressive neurodegenerative disease that affects neurons (nerve cells) in the brain and the spinal cord. Eventually, people with ALS lose the ability to initiate and control muscle movement, which often leads to total paralysis and death within two to five years of diagnosis. There is no cure and no life-prolonging treatments for the disease. 

TDP-43 is a protein with normal roles in processing RNA, the cellular messenger for DNA. Misfolded TDP-43 is found in protein aggregates in the motor neurons of almost all people with ALS. The consequence of this misfolding and aggregation is not clear. To perform its normal job, TDP-43 must convert between alternative folded states, analogous to the open and closed states of an umbrella. In this study, researchers found during the conversion between these states, TDP-43 entered an intermediate state in which there was a high risk of becoming misfolded and losing its function, the first step in forming aggregates. The likelihood of misfolding could be increased by cellular stresses known to be associated with ALS.

“This work gives us new information about the normal behavior of this important protein,” said Lucie Bruijn, Ph.D., Chief Scientist for The Association. “By understanding the risk factors for misfolding, we may be able to design treatments that lessen those risks, while still allowing TDP-43 to do its job.”

The research was performed by Brian Mackness, Ph.D., under the leadership of Jill Zitzewitz, Ph.D., both of University of Massachusetts Medical School in Worcester, Mass., and was funded by The Jeff Kaufman Fund of the The ALS Association, Wisconsin Chapter.

About The ALS Association
The ALS Association is the only national non-profit organization fighting Lou Gehrig’s Disease on every front.  By leading the way in global research, providing assistance for people with ALS through a nationwide network of chapters, coordinating multidisciplinary care through certified clinical care centers, and fostering government partnerships, The Association builds hope and enhances quality of life while aggressively searching for new treatments and a cure.  For more information about The ALS Association, visit our website at

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