Small-Molecule-Mediated Upregulation of G3BP1 as a Therapy for ALS
Abstract
Amyotrophic lateral sclerosis (ALS) also known as Lou Gehrig s Disease, is a neurodegenerative disease for which there is no effective treatment. The disease affects motor neurons, which are nerve cells that control the voluntary movement of muscles. These cells are under constant stress in ALS patients and eventually die, resulting in paralysis and death. An ancient and critical cellular response is to protect cells by temporarily halting the production of proteins (functional components of cells). This is accomplished by the formation of small containing cytoplasmic particles, called stress granules. Disruption in the formation or disassembly of these granules results in cell death, including the types of cells that are lost in ALS, and this process may be defective in ALS. Prior work suggests that the redistribution of TDP-43 from its usual location in the nucleus to the cytoplasm is associated with an impaired stress granule response in neurons. This proposal aims to restore this essential cell survival mechanism using small molecules as a potential therapeutic strategy for ALS by exploiting recent findings of how it is regulated. Since TDP-43 mislocalization happens in the majority of cases, it is anticipated that this small molecule drug approach would be broadly applicable to the majority of people affected by ALS. This proposal will enable lead selection and provide a critical appraisal of whether targeting this stress response could be a viable therapeutic strategy using mouse models, and thus pave the way for downstream studies to move this approach closer to clinical trial.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310262
Entities
People
- Dominque Cheneval
Organizations
- United States Army