Tau-Mediated Disruption of the Spliceosome Triggers Cryptic RNA Splicing and Neurodegeneration in Alzheimer's Disease.
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ID: 59220
2019
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.
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| Authors | Hsieh, Yi-Chen;Guo, Caiwei;Yalamanchili, Hari K;Abreha, Measho;Al-Ouran, Rami;Li, Yarong;Dammer, Eric B;Lah, James J;Levey, Allan I;Bennett, David A;De Jager, Philip L;Seyfried, Nicholas T;Liu, Zhandong;Shulman, Joshua M; |
| Journal | Cell reports |
| Year | 2019 |
| DOI | S2211-1247(19)31166-0 |
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