Tau-Mediated Disruption of the Spliceosome Triggers Cryptic RNA Splicing and Neurodegeneration in Alzheimer’s Disease

Abstract

Summary: In Alzheimer’s disease (AD), spliceosomal proteins with critical roles in RNA processing aberrantly aggregate and mislocalize to Tau neurofibrillary tangles. We test the hypothesis that Tau-spliceosome interactions disrupt pre-mRNA splicing in AD. In human postmortem brain with AD pathology, Tau coimmunoprecipitates with spliceosomal components. In Drosophila, pan-neuronal Tau expression triggers reductions in multiple core and U1-specific spliceosomal proteins, and genetic disruption of these factors, including SmB, U1-70K, and U1A, enhances Tau-mediated neurodegeneration. We further show that loss of function in SmB, encoding a core spliceosomal protein, causes decreased survival, progressive locomotor impairment, and neuronal loss, independent of Tau toxicity. Lastly, RNA sequencing reveals a similar profile of mRNA splicing errors in SmB mutant and Tau transgenic flies, including intron retention and non-annotated cryptic splice junctions. In human brains, we confirm cryptic splicing errors in association with neurofibrillary tangle burden. Our results implicate spliceosome disruption and the resulting transcriptome perturbation in Tau-mediated neurodegeneration in AD. : Integrating studies of human postmortem brain tissue and Drosophila melanogaster models, Hsieh et al. show that Alzheimer’s disease Tau neurofibrillary tangle pathology disrupts spliceosome activity. RNA-splicing errors, including intron retention and non-annotated cryptic junctions, and resulting transcriptome perturbation are implicated in Tau-mediated neurodegenerative mechanisms. Keywords: Alzheimer’s disease, neurodegeneration, Tau, neurofibrillary tangles, spliceosome, RNA splicing, cryptic splicing, intron retention, SmB, U1-70K