UC Irvine researchers uncover altered RNA processing in ALS

UC Irvine researchers have conducted a study to better understand the molecular basis of Amyotrophe Lateral Sclerosis (ALS), a neurodegenerative disorder where patients lose the ability to move, weak and wheelchair -bound before they can no longer breathe.

“Like is a devastating disease that often striking patients in the forty, 50 or 60s,” says Distingughed Professor in 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 urgently need treatments to delay the progression of this disease, which is a death sentence for patients who have little hope to take a lot of benefit from the current approved therapies.”

Earlier research into abnormalities of the processing of messenger-rna’s (mrna’s) has shown that when TDP-43, an important protein that is involved in the pathogenesis of ALS, is lost from the core of neurons, mrna’s are not split correctly.

We have discovered that a different aspect of RNA processing, known as polyadylering, has also been changed to as a result of TDP-43 function loss in the core. “

Eric Arnold, PhD, assistant project scientist in the La Spada Lab

The findings appear in a paper published in the number of 2 June 2025, Journal of Clinical Investigation. “When an RNA is transcribed from DNA, a long tail of adeninerests is added (the Polya tail) and the place where that happens, the length of the 3 non -praised area (3’utr) determines,” explains Arnold. The researchers discovered that there is pathological alternative polyadylering (APA) as resulting in abnormally long or short 3’utrs, who influence the function of mrna’s.

“We have identified one gene, Mark3, where pathological extension of the 3’utr as a result of APA results in the Mark3 -protein ending in the wrong place in the Neuron, which will influence his ability to function normally,” says Sebastian Michels, MD, a former postdoctoral guy. “By identifying genes of which MRNAs are dysfunctional by abnormal polyady ling, we can investigate whether correction of abnormal gene function can be a way to prevent motor neurons from working properly and ultimately dying.”

The following steps include screening about 300 different genes that have been identified in the study as undergoing abnormal polyadenylation in ALS. The researchers want to determine whether one 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 after the diagnosis, and 90% of the cases are sporadic, which means that they show up in patients without a direct family history of the disease,” says La Spada. “This is a perfect example of how fundamental research into the molecular substantiation of a disease can result in the development of therapy.”