An AI-predicted chemical compound suppresses ATXN1 protein aggregation and rescues iNSC-derived SCA1 neurons from cell death

Abstract

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by CAG repeat expansions in the ATXN1 gene. The mutant ataxin-1 (ATXN1) protein forms toxic oligomers which slowly aggregate into larger insoluble inclusions within the nucleus. The AXH domain of ATXN1 is suggested to play a critical role in the aggregation of its mutant isoform. Currently, there is no treatment for SCA1. Aims: 1. Identification of chemical compound which would bind to the AXH domain and might suppress its dimerization and polyQ-expanded ATXN1 aggregation 2. Generation and characterization of iNSC-derived neurons from SCA1 patients 3. Validation of the AI-predicted novel compound in aggregation and cell death on iNSC-derived SCA1 neurons