Rogue Proteins May Underlie Some ALS and Frontotemporal Dementia Cases

Monday, August 27, 2018 - 10:30
Researchers found clumps of non-functioning hnRNP H and at least three other RNA-binding proteins in the brain cells of people who had died with ALS, frontotemporal dementia or both. Bright red clumps of hnRNP H can be seen in the spinal cord motor neurons at left. Healthy neurons are shown at right. (Images: Aarti Sharma /Columbia University)

Researchers found clumps of non-functioning hnRNP H and at least three other RNA-binding proteins in the brain cells of people who had died with ALS, frontotemporal dementia or both. Bright red clumps of hnRNP H can be seen in the spinal cord motor neurons at left. Healthy neurons are shown at right. (Images: Aarti Sharma /Columbia University) 

Discovery May Lead to New Ways of Diagnosing and Treating Both Diseases

ALS — amyotrophic lateral sclerosis — is a neurodegenerative disease that attacks motor neurons in the brain and spinal cord, slowly robbing its victims of their ability to walk, talk, breathe and swallow. In a cruel twist, some ALS patients also develop frontotemporal dementia, a disease that destroys an entirely different set of brain cells — cortical neurons — leading to personality changes, among other effects.

Inherited forms of both diseases have been traced to gene mutations associated with an abnormal buildup of the RNA-binding protein, TDP-43, in the brain.  Now, in a study in the journal eLife, Columbia University and New York Genome Center researchers show that TDP-43 and at least three other RNA-binding proteins appear to run similarly amok in ALS and dementia patients without the mutation. Their finding suggests that the dominant form of hereditary ALS and frontotemporal dementia may share molecular underpinnings with far more common versions of ALS and dementia that have no known genetic basis. 

“It turns out that if you analyze the biochemical properties of RNA-binding proteins you see it’s not just TDP-43 but several others that are also perturbed,” says Aaron Gitler, a genetics professor at Stanford University who discusses the study in the same issue of eLife. “This is a new concept in how we think about these diseases – not just as TDP-43 diseases, but as RNA-binding protein diseases.”

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