ALS Association-funded Study Identifies Potential Therapeutic Target in RNA Enzyme

A new study funded in part by The ALS Association has revealed a potential new target for therapy to treat amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s Disease.  This study, published in Nature Genetics on October 28, shows that lowering the level of a cellular enzyme reduces the disease-causing activity of a major ALS-related protein called TDP-43.

Most people with ALS develop clumps of excess TDP-43 protein within their motor neurons, nerve cells that control movement.  The protein clumps, or aggregates, are believed to be toxic to the neurons, through unknown mechanisms.  ALS occurs when motor neurons die.

“This finding shows us there may be a variety of ways to target the excess TDP-43 seen in most people with ALS,” said Lucie Bruijn, Ph.D., Chief Scientist for The ALS Association.  “That is encouraging news for the development of new therapies.”

The new study was conducted by Maria Armakola, a graduate student at Stanford University in Palo Alto, Calif., and Matthew Higgins, Ph.D., of the Gladstone Institute of Cardiovascular Disease in San Francisco, Calif., under the direction of Aaron Gitler, Ph.D., of Stanford and Robert Farese, Jr., M.D., of the Gladstone Institute.

The study was conducted in yeast cells at risk for dying from TDP-43 aggregates or clumps.  The researchers found that deletion of the cellular enzyme called the “RNA lariat debranching enzyme” rescued the at-risk cells.  The enzyme normally destroys excess RNA.  Without the enzyme, cells accumulate small pieces of RNA, which, the researchers suggest, may act as “decoys” to trap excess TDP-43, thus preventing it from aggregating and causing toxicity.  The same protective effect was seen in rodent cells, an encouraging sign that a similar strategy may be effective in human cells.

“There will be much more work to do to determine if this finding can be developed into a therapy for ALS,” Dr. Bruijn said.  “Importantly, though, this work may also tell us more about how TDP-43 causes disease and suggest other ways to interrupt it from doing so. That should accelerate the development of new treatments against ALS.”

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Nature Genetics