UC Irvine investigators sought to elucidate the molecular underpinnings of amyotrophic lateral sclerosis (ALS), a neurodegenerative condition in which patients progressively lose motor function, ultimately becoming wheelchair-bound and succumbing to respiratory failure. Distinguished Professor of Pathology Albert La Spada, MD, PhD, emphasized that ALS typically manifests in individuals in their 40s through 60s and lamented the paucity of therapies capable of meaningfully slowing its inexorable progression.

Prior studies had established that loss of nuclear TDP-43—a protein central to ALS pathology—disrupts normal messenger RNA (mRNA) splicing in neurons. In their new work, the team, which included collaborators from the University of Ulm, the Mayo Clinic, and NYU, demonstrated that TDP-43 depletion also perturbs polyadenylation, another critical step in RNA maturation. Assistant Project Scientist Eric Arnold, PhD, explained that polyadenylation site selection determines the length of an mRNA’s 3′ untranslated region (3′UTR), and that in ALS models, pathological alternative polyadenylation (APA) produces abnormally long or short 3′UTRs, compromising mRNA stability and function.

Their findings—published June 2, 2025, in the Journal of Clinical Investigation—include detailed analyses of APA events in affected neurons. Pathological APA was shown to lengthen or shorten 3′UTRs in hundreds of transcripts. Among these, the MARK3 gene exhibited pathological 3′UTR extension, causing mislocalization of the MARK3 protein within motor neurons and undermining its normal role in neuronal maintenance. Former postdoctoral fellow Sebastian Michels, MD, noted that correcting aberrant polyadenylation in such genes could offer a strategy to preserve motor-neuron function and viability in ALS patients.

Looking ahead, the research team plans to screen approximately 300 genes identified as APA-affected in ALS, with the goal of pinpointing therapeutic targets amenable to genetic or pharmacological modulation. Professor La Spada underscored that, because most ALS cases arise sporadically—with patients typically dying within two to three years of diagnosis—basic research into molecular disease mechanisms remains essential to uncovering novel treatment avenues.

Source: https://medschool.uci.edu/news/findings-offer-hope-future-als-treatment