High-throughput imaging screen to restore TDP-43 localization in aged neurons
Description: The protein TDP-43 is one of the most important players in ALS: more than 95% of ALS patients have aggregates of TDP-43 within their motor neurons. This aggregation is thought to arise from chronic mislocalization of TDP-43 from nucleus – its typical home – to the cytoplasm. Importantly, TDP-43 mislocalization is known to cause major changes in the RNA biology of motor neurons that contribute to ALS pathology. However, it is unclear how exactly TDP-43 mislocalizes from the nucleus to the cytoplasm. We recently employed a novel differentiation approach that allows us to make aged neurons from donor fibroblasts, and our preliminary results indicate that aging alone is a major contributor to TDP-43 mislocalization. Therefore, we propose to leverage our differentiation approach to identify compounds and small-molecules that might restore nuclear TDP-43, which would reverse a major risk factor for ALS. Our small-molecule screen design is relatively simple: we plan to generate >20 million aged neurons via our differentiation approach, stain for TDP-43 localization, and use computational algorithms to calculate the nuclear localization of TDP-43. Our screen will focus on ~4000 known bioactive compounds, which will enable us to rapidly transition to preclinical studies for any hits. In addition to the preclinical angle, the compounds we identify could be used to identify which proteins and RNAs help maintain nuclear TDP-43, and we could apply our screen to other ALS-associated proteins that are mislocalized due to aging like hnRNPA1.
Funder: ALS Association
Amount: $50,000
Funding type: award
Start date: 2025-02-01
End date: 2026-01-31
Investigator: Kevin Rhine
Institution: The Regents of the University of California, San Diego
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Funded outputs count: 1
Funder award ID: 26-SGP-764
OpenAlex ID: G1705570925