Relevance of stress granule dynamics to ALS pathogenesis in vivo

ALS places constant stress on motor neurons, the nerve cells responsible for voluntary muscle movement, causing them to deteriorate and die. G3BP1 is a crucial protein in the formation of stress granules, protective structures that healthy cells produce when exposed to stress. These stress granules safeguard vulnerable RNA molecules, which play a vital role in translating genetic instructions and overseeing protein production, protecting them from damage. Recent evidence suggests that the disruption of proper stress granule dynamics may play a central role in the processes underlying ALS.

Traditionally, most lines of research exploring the role of stress granules in ALS have sought to inhibit their formation as a potential therapeutic approach. However, recent evidence from Dr. Vande Velde’s lab raises questions about the validity of this approach. They hypothesize that impaired stress granule dynamics may make motor neurons more vulnerable, suggesting that strategies to boost stress granule formation could be more valuable in treating the disease. Additionally, the team has found that TDP-43 dysfunction, a feature present in 97 per cent of all ALS cases, negatively impacts stress granule dynamics.

With this award, Dr. Vande Velde will assess the impact of age and environmental stress on stress granule biology and the development of ALS-related symptoms in a mouse model mimicking TDP-43 abnormalities. Furthermore, the team will investigate whether modifying key regulators of stress granules, such as G3BP1 or eIFA1, can rescue their formation in mice. Overall, the project seeks to deepen our understanding of the molecular mechanisms underlying ALS and explore new therapeutic possibilities. If successful, the outcomes of this study could lay the foundation for future therapeutic strategies aimed at restoring stress granule dynamics in ALS.