RT Journal Article
SR Electronic
T1 Tau-mediated Disruption of the Spliceosome Triggers Cryptic RNA-splicing and Neurodegeneration in Alzheimer’s Disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 514927
DO 10.1101/514927
A1 Yi-Chen Hsieh
A1 Caiwei Guo
A1 Hari K. Yalamanchili
A1 Measho Abreha
A1 Rami Al-Ouran
A1 Yarong Li
A1 Eric B. Dammer
A1 James J. Lah
A1 Allan I. Levey
A1 David A. Bennett
A1 Philip L. De Jager
A1 Nicholas T. Seyfried
A1 Zhandong Liu
A1 Joshua M. Shulman
YR 2019
UL http://biorxiv.org/content/early/2019/01/09/514927.abstract
AB 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 core components. In Drosophila models, pan-neuronal Tau expression triggers reductions in 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 pathologic burden. Our results implicate spliceosome disruption and perturbations of the neuronal transcriptome in Tau-mediated neurodegeneration in AD.