RRC ID 59160
Author Hsieh YC, Guo C, Yalamanchili HK, Abreha M, Al-Ouran R, Li Y, Dammer EB, Lah JJ, Levey AI, Bennett DA, De Jager PL, Seyfried NT, Liu Z, Shulman JM.
Title Tau-Mediated Disruption of the Spliceosome Triggers Cryptic RNA Splicing and Neurodegeneration in Alzheimer's Disease.
Journal Cell Rep
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.
Volume 29(2)
Pages 301-316.e10
Published 2019-10-8
DOI 10.1016/j.celrep.2019.08.104
PII S2211-1247(19)31166-0
PMID 31597093
PMC PMC6919331
MeSH Alzheimer Disease / complications Alzheimer Disease / genetics* Alzheimer Disease / pathology Alzheimer Disease / physiopathology Animals Brain / metabolism Brain / pathology Brain / physiopathology Drosophila / metabolism* Drosophila Proteins / metabolism Humans Models, Biological Motor Activity Nerve Degeneration / complications Nerve Degeneration / genetics* Nerve Degeneration / physiopathology RNA Splicing / genetics* Ribonucleoproteins, Small Nuclear / metabolism Spliceosomes / metabolism* tau Proteins / metabolism*
IF 8.109
Times Cited 7
Drosophila DGRC#122076