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Hsieh, Y.C., Guo, C., Yalamanchili, H.K., Abreha, M., Al-Ouran, R., Li, Y., Dammer, E.B., Lah, J.J., Levey, A.I., Bennett, D.A., De Jager, P.L., Seyfried, N.T., Liu, Z., Shulman, J.M. (2019). Tau-Mediated Disruption of the Spliceosome Triggers Cryptic RNA Splicing and Neurodegeneration in Alzheimer's Disease.  Cell Rep. 29(2): 301--316.e10.
FlyBase ID
FBrf0243709
Publication Type
Research paper
Abstract

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.

PubMed ID
PubMed Central ID
PMC6919331 (PMC) (EuropePMC)
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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Cell Rep.
    Title
    Cell reports
    ISBN/ISSN
    2211-1247
    Data From Reference
    Aberrations (2)
    Alleles (47)
    Genes (26)
    Human Disease Models (2)
    Natural transposons (1)
    Insertions (5)
    Experimental Tools (1)
    Transgenic Constructs (41)