Novel Therapeutics Targeting Stress Granules for C9orf72-Mediated ALS
Abstract
Stress granules (SGs) play a key role in amyotrophic lateral sclerosis (ALS) pathogenesis by multiple mechanisms, including the induction of protein aggregation. Thus, targeting SG formation holds great promise in treating ALS. However, previous SG inhibitors that are beneficial to the nervous system have severe side-effects, which prevents their clinical use. This is partially because the target proteins of previous SG inhibitors also have important roles in other parts of the body than the nervous system. Thus, we need to identify additional SG-related targets for ALS therapeutic development. Notably, previous studies have identified >300 additional proteins implicated in SG formation, but whether these proteins can be used as therapeutic targets and whether their inhibitors can be potential ALS drugs are unknown. Using fruit fly and patient-induced pluripotent stem cell-derived motor neurons as model systems, we will screen these proteins to identify novel therapeutic target and/or drug candidates, which can be verified in future preclinical (vertebrate animals) and clinical studies. We use fly and iPSN models of C9ORF72-mediated ALS (c9ALS), the most common type of familial ALS, in which SGs have been shown to play an important role. Upon the accomplishment of this project, we will identify potential therapeutic targets and/or drugs that can be further tested in vertebrate animal models and then in patients of c9ALS. Given the general role of SGs in the vast majority of ALS types, we suggest that our findings can also be applied to other ALS types, including sporadic ALS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110082
Entities
People
- Ke Zhang
Organizations
- Mayo Clinic Hospital – Jacksonville
- United States Army