PT - JOURNAL ARTICLE AU - Denethi Wijegunawardana AU - Sonali S. Vishal AU - Neha Venkatesh AU - Pallavi P. Gopal TI - Ataxin-2 polyglutamine expansions aberrantly sequester TDP-43, drive ribonucleoprotein condensate transport dysfunction and suppress local translation AID - 10.1101/2023.01.30.526372 DP - 2023 Jan 01 TA - bioRxiv PG - 2023.01.30.526372 4099 - http://biorxiv.org/content/early/2023/01/31/2023.01.30.526372.short 4100 - http://biorxiv.org/content/early/2023/01/31/2023.01.30.526372.full AB - Altered RNA metabolism is a common pathogenic mechanism linked to familial and sporadic Amyotrophic lateral sclerosis (ALS). ALS is characterized by mislocalization and aggregation of TDP-43, an RNA-binding protein (RBP) with multiple roles in post-transcriptional RNA processing. Recent studies have identified genetic interactions between TDP-43 and Ataxin-2, a polyglutamine (polyQ) RBP in which intermediate length polyQ expansions confer increased ALS risk. Here, we used live-cell confocal imaging, photobleaching and translation reporter assays to study the localization, transport dynamics and mRNA regulatory functions of TDP-43/Ataxin-2 in rodent primary cortical neurons. We show that Ataxin-2 polyQ expansions aberrantly sequester TDP-43 within ribonucleoprotein (RNP) condensates, and disrupt both its motility along the axon and liquid-like properties. Our data suggest that Ataxin-2 governs motility and translation of neuronal RNP condensates and that Ataxin-2 polyQ expansions fundamentally perturb spatial localization of mRNA and suppress local translation. Overall, these results indicate Ataxin-2 polyQ expansions have detrimental effects on stability, localization, and translation of transcripts critical for axonal and cytoskeletal integrity, particularly important for motor neurons.Competing Interest StatementThe authors have declared no competing interest.