Key Gene Expression Disruption Central to ALS Development Unveiled

Recent research from Tohoku University and Keio University has uncovered a significant molecular mechanism underlying amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease characterized by progressive muscle weakness. The team focused on the gene UNC13A, essential for neuronal communication, as a common target affected across various forms of ALS. Their study revealed that loss of function in multiple ALS-associated RNA-binding proteins leads to a decrease in UNC13A expression through two distinct pathways. One pathway involves the inclusion of a cryptic exon in the UNC13A mRNA, resulting in its destabilization and reduced protein production. The other pathway is a novel mechanism where the depletion of proteins like FUS, MATR3, or hnRNPA1 causes an increase in REST, a transcriptional repressor that suppresses UNC13A transcription. This suppression of UNC13A could play a crucial role in the disease's progression.

The researchers validated their findings by analyzing motor neurons derived from ALS patient iPS cells and spinal cord tissues from autopsies, confirming elevated REST levels in clinical samples. This convergence of different genetic mutations on a shared downstream effect, UNC13A deficiency, highlights its central role in ALS pathogenesis. Targeting the pathways that preserve UNC13A expression or modulate REST activity could open new avenues for broad-spectrum therapeutic strategies that may slow disease progression.

Understanding these mechanisms enhances our knowledge of ALS's complex molecular landscape and paves the way for potential treatments that address common molecular vulnerabilities across different ALS forms. Continued research in this direction offers hope for developing interventions that could slow or halt the progression of ALS, improving quality of life for patients.

Source: https://medicalxpress.com/news/2025-07-common-gene-disruption-heart-als.html