Molecular determinants and modifiers of Matrin-3 toxicity, condensate dynamics, and droplet morphology.

ABSTRACT: Matrin-3 (MATR3) is a DNA- and RNA-binding protein implicated in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and distal myopathy. Here, we report the development of a yeast model of MATR3 proteotoxicity and aggregation. MATR3 is toxic and forms dynamic shell-like nuclear condensates in yeast. Disease-associated mutations in MATR3 impair condensate dynamics and disrupt condensate morphology. MATR3 toxicity is largely driven by its RNA-recognitions motifs (RRMs). Further, deletion of one or both RRMs drives coalescence of these condensates. Aberrant phase separation of several different RBPs underpins ALS/FTD, and we have engineered Hsp104 variants to reverse this misfolding. Here, we demonstrate that these same variants also counter MATR3 toxicity. We suggest that th

SUBMITTER: Sprunger ML 

PROVIDER: S-EPMC8889142 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature