Findings offer hope for future ALS treatment

rvine, Calif., June 3, 2025 — UC Irvine researchers conducted a study to better understand the molecular basis of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder in which patients lose the ability to move, becoming weak and wheelchair bound before dying because they can no longer breathe.

“ALS is a devastating disease commonly striking patients in their 40s, 50s or 60s,” says Distinguished Professor of pathology Albert La Spada, MD, PhD, who worked on the study with colleagues from UC Irvine; the University of Ulm, Germany; the Mayo Clinic; and NYU. “We are in dire need of treatments to slow the progression of this disease, which is a death sentence for patients who have little hope of benefitting much from current approved therapies.”

Previous research into abnormalities of the processing of messenger RNAs (mRNAs) has shown that when TDP-43, a key protein involved in the pathogenesis of ALS, is lost from the nucleus of neurons, mRNAs do not get spliced properly.

“We discovered that another aspect of RNA processing, known as polyadenylation, is also altered in ALS due to TDP-43 loss of function in the nucleus,” says Eric Arnold, PhD, an assistant project scientist in the La Spada Lab.

The findings appear in a paper published in the June 2, 2025, issue of the Journal of Clinical Investigation. “When an RNA is transcribed from DNA, a long tail of adenine residues is added (the polyA tail), and the site where that happens determines the length of the 3’ untranslated region (3’UTR),” explains Arnold. The researchers found that there is pathological alternative polyadenylation (APA) in ALS resulting in abnormally long or short 3’UTRs, which affects the function of mRNAs.

“We identified one gene, MARK3, where pathological lengthening of the 3’UTR due to APA results in the MARK3 protein ending in the wrong place in the neuron, which will affect its ability to function normally,” says Sebastian Michels, MD, a former postdoctoral fellow in the La Spada Lab. “By identifying genes whose mRNAs become dysfunctional due to abnormal polyadenylation, we can examine if correction of the abnormal gene function might be a way to prevent motor neurons in ALS patients from not working properly and eventually dying.”

The next steps involve screening roughly 300 different genes identified in the study as undergoing abnormal polyadenylation in ALS. The researchers aim to determine whether any of the genes are candidates for therapeutic modulation in the hope of developing new treatments for patients suffering from ALS.

“Most patients die within two to three years of being diagnosed, and 90% of cases are sporadic, meaning they show up in patients without a direct family history of the disease,” says La Spada. “This is a perfect example of how basic research into the molecular underpinnings of a disease can yield targets for therapy development.”

About the UC Irvine School of Medicine

Each year, the UC Irvine School of Medicine educates more than 500 medical students and nearly 150 PhD and MS students. More than 750 residents and fellows are trained at the UCI Medical Center and affiliated institutions. The School of Medicine offers multiple MD, PhD and MS degrees, and students are encouraged to pursue an expansive range of interests and options. The UC Irvine School of Medicine is accredited by the Liaison Committee on Medical Accreditation and ranks among the top 50 nationwide for research. For more information, visit medschool.uci.edu.