Abstract
Alzheimer's disease (AD) and other tauopathies are neurodegenerative disorders with devastating consequences for cognition and memory. Pathogenic accumulation of tau can be modeled in Caenorhabditis elegans, which recapitulate human neurodegeneration including aging-dependent accumulation of phosphorylated tau, tau aggregation, neuronal dysfunction, and neuron degeneration. Using forward genetic screens to identify genes modulating tau pathology, we identified a single point mutation in dib-1 that ameliorates tau-driven behavioral defects, prevents neurodegeneration, and decreases tau protein levels. The dib-1 gene encodes a small, highly conserved protein, known as TXNL4A in humans, and participates in mRNA splicing via the U4/U6.U5 tri-snRNP. Notably, heterozygous loss of prp-8, a neighboring protein within the tri-snRNP, also prevents tau-driven neurodegeneration. RNA sequencing of dib-1 mutants demonstrates widespread intron retention consistent with disruption of tri-snRNP functions. Disruption of nonsense-mediated decay further rescues tau-driven phenotypes only in the presence of the dib-1 mutation. TXNL4A levels are decreased in AD in human frontal cortex, demonstrating the translational relevance of dib-1. Taken together, these findings suggest pathological tau impacts splicing function, and spliceosomal activity modulation can ameliorate tauopathy.