Shared Disease Mechanism Identified in Some ALS, Frontotemporal Dementia Cases

Amyotrophic lateral sclerosis and frontotemporal dementia exhibit key similarities in underlying molecular mechanisms tied to the dysfunction of RNA-binding proteins.

Individuals with amyotrophic lateral sclerosis (ALS) sometimes also develop frontotemporal dementia (FTD), which is marked by the degeneration of neurons in the frontal cortex. A new study published in eLife suggests that the diseases may share underlying mechanisms associated with the common loss of functioning RNA-binding proteins.

In some cases, the co-occurrence of the 2 diseases is the result of a dominantly inherited disease mutation that increases the chances of ALS patients being diagnosed with FTD, according to the study. Both diseases have been traced to gene mutations associated with an abnormal buildup of the RNA-binding protein TDP-43 in the brain.

In the new study, the findings suggest that some ALS/FTD cases both with and without the disease-associated mutation involve rogue RNA-binding proteins that stop the regulation of gene expression.

According to the researchers, mutation-free patients represent the majority of ALS and FTD cases. Researchers from Columbia University and New York Genome Center have found that TDP-43 and at least 3 other RNA-binding proteins appeared to lose functioning in ALS/FTD patients without the mutation.

“This is a new concept in how we think about these diseases — not just as TDP-43 diseases, but as RNA-binding protein diseases,” Aaron Gitler, PhD, a genetic professor at Stanford University, said in a press release.

For the study, the researchers analyzed the brains of 50 individuals who had died with 1 or both diseases. More than half of the brain held large amounts of biochemically insoluble hnRNP H and 3 other RNA-binding proteins, TDP-43, FUS, and hnRNP A1, indicating that all had stopped regulating gene expression, according to the study.

“RNA-binding proteins control how much protein a gene makes,” senior author James Manley, PhD, a molecular biology professor at Columbia University, said in a press release. “This process goes seriously awry when these aggregates are found.”

Despite the findings, the researchers noted that there are still many unknowns, including the cause of the rogue proteins and why motor and cortical neurons are especially sensitive.

The findings point to the possibility of 2 forms of ALS, a form in which the RNA-binding function is disrupted and another with a still-unknown mechanism, the researchers reported. Additionally, the results indicate that diagnosis methods such as a blood test or other noninvasive ways to detect ALS and frontotemporal dementia could soon be a reality, according to the study.

“Our data suggests that we may be able to distinguish 1 subpopulation of ALS patients from the other,” study coauthor Neil Shneider, MD, PhD, a neurology professor who heads Columbia University Irving Medical Center’s Eleanor and Lou Gehrig ALS Center, said in a press release. “This could lead to a therapeutic intervention that works selectively on those patients.”

References

Conlon EG, Fagegaltier D, Agius P, et al. Unexpected similarities between C90ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism. eLife. 2018. DOI: 10.7554/eLife.37754

Rogue Proteins May Underlie Some ALS and Frontotemporal Dementia Cases, Says Study [news release]. Columbia University’s website. http://news.columbia.edu/content/1984. Accessed August 21, 2018.