@article{d3598044251648418385b5804470196f,
title = "Alzheimer{\textquoteright}s disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment",
abstract = "Recent proteome and transcriptome profiling of Alzheimer{\textquoteright}s disease (AD) brains reveals RNA splicing dysfunction and U1 small nuclear ribonucleoprotein (snRNP) pathology containing U1-70K and its N-terminal 40-KDa fragment (N40K). Here we present a causative role of U1 snRNP dysfunction to neurodegeneration in primary neurons and transgenic mice (N40K-Tg), in which N40K expression exerts a dominant-negative effect to downregulate full-length U1-70K. N40K-Tg recapitulates N40K insolubility, erroneous splicing events, neuronal degeneration and cognitive impairment. Specifically, N40K-Tg shows the reduction of GABAergic synapse components (for example, the GABA receptor subunit of GABRA2) and concomitant postsynaptic hyperexcitability that is rescued by a GABA receptor agonist. Crossing of N40K-Tg and the 5xFAD amyloidosis model indicates that the RNA splicing defect synergizes with the amyloid cascade to remodel the brain transcriptome and proteome, deregulate synaptic proteins and accelerate cognitive decline. Thus, our results support the contribution of U1 snRNP-mediated splicing dysfunction to AD pathogenesis.",
author = "Chen, {Ping Chung} and Xian Han and Shaw, {Timothy I.} and Yingxue Fu and Huan Sun and Mingming Niu and Zhen Wang and Yun Jiao and Teubner, {Brett J.W.} and Donnie Eddins and Beloate, {Lauren N.} and Bing Bai and Joseph Mertz and Yuxin Li and Cho, {Ji Hoon} and Xusheng Wang and Zhiping Wu and Danting Liu and Suresh Poudel and Yuan, {Zuo Fei} and Ariana Mancieri and Jonathan Low and Lee, {Hyeong Min} and Patton, {Mary H.} and Earls, {Laurie R.} and Elizabeth Stewart and Peter Vogel and Yawei Hui and Shibiao Wan and Bennett, {David A.} and Serrano, {Geidy E.} and Beach, {Thomas G.} and Dyer, {Michael A.} and Smeyne, {Richard J.} and Tudor Moldoveanu and Taosheng Chen and Gang Wu and Zakharenko, {Stanislav S.} and Gang Yu and Junmin Peng",
note = "Funding Information: We thank all other laboratory and center members for discussion and technical support. We thank St Jude Shared Resources and Core Facilities, including the Animal Research Center, Transgenic/Gene Knockout, In Vivo Imaging and Therapeutics, Veterinary Pathology, Cytogenetics, Genome Sequencing, Proteomics and Metabolomics, Applied Bioinformatics and Cell and Tissue Imaging. We also thank J. Jankowsky for providing plasmids, I. Bayazitov for electrophysiology, F. Zheng for the discussion of behavior studies, A. Hemphill for western blots of replicates during revision and I. Chen for helpful discussion and guidance. This work was partially supported by National Institutes of Health grants R01AG047928 (J.P.), R01AG053987 (J.P.), RF1AG068581 (J.P.), RF1AG064909 (G.Y. and J.P.), U54NS110435 (J.P.), U19AG069701 (J.P.), R01MH095810 (S.S.Z.) and American Lebanese Syrian Associated Charities. The Banner Sun Health Research Institute Brain and Body Donation Program was supported by National Institutes of Health grants U24NS072026, P30AG072980, P30AG19610, the Arizona Department of Health Services, the Arizona Biomedical Research Commission and the Michael J. Fox Foundation for Parkinson{\textquoteright}s Research. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2022",
month = oct,
doi = "10.1038/s43587-022-00290-0",
language = "English (US)",
volume = "2",
pages = "923--940",
journal = "Nature Aging",
issn = "2662-8465",
publisher = "Springer",
number = "10",
}