Journal
CELL REPORTS
Volume 29, Issue 2, Pages 301-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.08.104
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Funding
- NIH [R01AG053960, R01AG036836, R01AG050631, R01AG057339, U01AG046161, P30AG10161, R01AG15819, R01AG17917, U01AG46152, R01GM120033, U01AG061357, P30CA125123, U54HD083092]
- Huffington Foundation
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital
- Burroughs Wellcome Fund
- Cancer Prevention Research Institute of Texas [RP170387]
- Houston Endowment
- Belfer Neurodegenerative Disease Consortium
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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 spliceosomedisruption and the resulting transcriptome perturbation in Tau-mediated neurodegeneration in AD.
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