New research identifies critical gene for treatment

Amyotrophic lateral sclerosis (ALS) – which you may know as the disease that affected Stephen Hawking – is a fatal neurodegenerative disease that causes progressive muscle weakness. A research team at Tohoku University and Keio University has uncovered a unifying mechanism in ALS revolving around the expression of UNC13A (a gene crucial for neuronal communication) that represents a common target for developing effective treatment strategies that could improve the lives of patients with ALS.

“Scientists still don’t fully understand the process behind the loss of motor neurons in ALS. ALS is known for its genetic heterogeneity – meaning that there are numerous possible combinations of genes and factors that could lead to ALS. This makes it difficult to develop a singular treatment that works for everyone.”

Yasuaki Watanabe, Assistant Professor, Tohoku University

For example, a hallmark of many ALS cases is the loss of TDP-43 (a nuclear RNA-binding protein) which causes widespread RNA dysregulation. However, many other ALS-linked proteins such as FUS, MATR3, and hnRNPA1 have also been implicated, each with differing pathological mechanisms. This diversity has long hindered the search for common therapeutic targets.

Led by Assistant Professor Yasuaki Watanabe and Professor Keiko Nakayama, Tohoku University, the team sought to identify a molecular pathway shared among different forms of ALS. They generated neural cell lines in which one of four key ALS-related RNA-binding proteins was depleted. In all cases, the expression of UNC13A was significantly reduced.

The study revealed two distinct molecular mechanisms underlying this reduction. One mechanism involves the inclusion of a cryptic exon in the UNC13A transcript, which leads to mRNA destabilization. The second was a completely new finding, which shows that the loss of FUS, MATR3, or hnRNPA1 causes overexpression of the transcriptional repressor REST. As the name implies, REST suppresses UNC13A gene transcription, making it unable to perform its usually helpful functions. This suppression may be what leads to the symptoms found in ALS.

To clarify whether these results mirrored what was really occurring in patients with ALS, the researchers looked at motor neurons derived from ALS patient iPS cells and in spinal cord tissues from ALS autopsy cases. Importantly, the researchers confirmed elevated REST levels, strengthening the clinical relevance of their findings.

This newly discovered convergence of distinct ALS-causing mutations on a single downstream effect–UNC13A deficiency–offers critical insight into the disease’s complexity. The results highlight UNC13A as a central hub in ALS pathogenesis and suggest that preserving its expression, or modulating REST activity, could represent promising therapeutic strategies.

“This study provides a valuable framework for developing broad-spectrum treatments that target shared molecular vulnerabilities in ALS,” says Nakayama.

As ALS progresses, patients’ muscles waste away until they eventually lose the ability to swallow or breathe. A treatment that could potentially slow down or prevent this progression in as many patients as possible represents a large stride forward in ALS research.