ALS Protein Risks Misfolding to Perform Its Normal Function

February 21, 2014

In ALS Association-supported work, researchers have shown that a prominent ALS-related protein, TDP-43, may misfold as a result of its normal function, an insight that may help tailor therapies designed to prevent misfolding.

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 unclear. 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 from the University of Massachusetts Medical School in Worcester, Mass., found during the conversion between these states that TDP-43 entered an intermediate state in which there was a high risk of its becoming misfolded and losing its function, which is the first step in forming aggregates. The likelihood of misfolding could be increased by cellular stresses known to be associated with the disease.

“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 study was published in the Journal of Biological Chemistry, and the research was performed by Brian Mackness, Ph.D., under the leadership of Jill Zitzewitz, Ph.D. This study was funded by The Jeff Kaufman Fund of the The ALS Association, Wisconsin Chapter.

Read the press release.

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