Amyotrophic lateral sclerosis (ALS) – which you may know as the disease that affected Stephen Hawking – is a deadly neurodegenerative disease that causes progressive muscle weakness. A research team at Tohoku University and Keio University has revealed a unifying mechanism in ALS that revolves around the expression of UNC13A (a critical neuronal communication gene) that represents a common goal for the development of effective treatment strategies that could improve the life strategies.
“Scientists still do not fully understand the process behind the loss of motor neurons in ALS. ALS is known for genetic heterogeneity – which means that there are many possible combinations of genes and factors that could lead to ALS.
Yasuaki Watanabe, Assistant Professor, Tohoku University
For example, a feature of many cases ALS is the loss of TDP-43 (nuclear RNA binding protein) which causes extensive RNA dysfunction. However, many other proteins associated with ALS such as FUS, MATR3 and HNRNPA1 have also been involved, each with different pathological mechanisms. This diversity has long prevented the search for common therapeutic goals.
Led by Assistant Professor Yasuaki Watanabe and Professor Keiko Nakayama, Tohoku University, the team tried to locate a molecular road that is shared between different forms of ALS. They created nerve cell rows in which one of the four basic RNA -related RNA -related proteins were exhausted. In all cases, the expression of UNC13A declined significantly.
The study revealed two separate molecular mechanisms that are a decrease in this reduction. A mechanism includes the inclusion of a cryptic cake in the UNC13A copy, which leads to mRNA destabilization. The second was a completely new finding, which shows that the loss of fus, Matr3 or HNRNPA1 causes an over -expression of the rest of the transcriptional repressor. As the name suggests, the rest suppresses UNC13A gene transcription, making it unable to perform its usually useful functions. This repression can be what leads to the symptoms found in ALS.
To clarify whether these results reflect what really happened to patients with ALS, the researchers examined the motor neurons coming from IPS patients and spinal cord tissues from cases of autopsy. It is important that the researchers have confirmed the increased levels of rest, enhancing the clinical significance of their findings.
This recently discovered convergence of distinct mutations that cause ALS in a single downstream UNCL13A-denominated the critical picture of the complexity of the disease. The results highlight UNC13A as a central hub in AlS pathogenesis and suggest that maintaining its expression or the formation of rest activity could represent promising therapeutic strategies.
“This study provides a valuable framework for the development of wide range of treatments aimed at common molecular vulnerabilities in ALS,” says Nakayama.
As ALS evolves, patients’ muscles waste until they eventually lose the ability to swallow or breathe. A treatment that could potentially slow down or prevent this development in as many patients as possible represents a large step forward in the ALS study.
Source:
Magazine reports:
Watanabe, Y, et al. (2025). ALS -related RNA -related proteins promote UNC13A transcript by downward adjustment. EMBO magazine. Doi.org/10.1038/S44318-025-00506-0
