Nuclear speckle proteins modulate tau toxicity

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 genetic tools to identify genes modulating tau pathology, we identified mutations in multiple nuclear speckle protein encoding genes that ameliorate tau-driven behavioral defects and prevent neurodegeneration. RNA sequencing reveals that these proteins, DIB-1, PRP-8, and ERH-1, have differential effects on gene expression, alternative splicing, and phosphorylated tau levels, highlighting how these proteins with similar roles may not share a single mechanism in alleviating tauopathy. Furthermore, levels of the human homologs of all three proteins are decreased in human Alzheimer’s disease samples, suggesting the translational relevance of this work. These findings point to nuclear proteins and mRNA dynamics as important drivers of tau toxicity and highlight the need to further investigate tau-mRNA interactions in neurodegenerative disease.