Alzheimer’s disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment

Ping Chung Chen; Xian Han; Timothy I. Shaw; Yingxue Fu; Huan Sun; Mingming Niu; Zhen Wang; Yun Jiao; Brett J.W. Teubner; Donnie Eddins; Lauren N. Beloate; Bing Bai; Joseph Mertz; Yuxin Li; Ji Hoon Cho; Xusheng Wang; Zhiping Wu; Danting Liu; Suresh Poudel; Zuo Fei Yuan; Ariana Mancieri; Jonathan Low; Hyeong Min Lee; Mary H. Patton; Laurie R. Earls; Elizabeth Stewart; Peter Vogel; Yawei Hui; Shibiao Wan; David A. Bennett; Geidy E. Serrano; Thomas G. Beach; Michael A. Dyer; Richard J. Smeyne; Tudor Moldoveanu; Taosheng Chen; Gang Wu; Stanislav S. Zakharenko; Gang Yu; Junmin Peng

doi:10.1038/s43587-022-00290-0

Alzheimer’s disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment

Ping Chung Chen, Xian Han, Timothy I. Shaw, Yingxue Fu, Huan Sun, Mingming Niu, Zhen Wang, Yun Jiao, Brett J.W. Teubner, Donnie Eddins, Lauren N. Beloate, Bing Bai, Joseph Mertz, Yuxin Li, Ji Hoon Cho, Xusheng Wang, Zhiping Wu, Danting Liu, Suresh Poudel, Zuo Fei YuanAriana Mancieri, Jonathan Low, Hyeong Min Lee, Mary H. Patton, Laurie R. Earls, Elizabeth Stewart, Peter Vogel, Yawei Hui, Shibiao Wan, David A. Bennett, Geidy E. Serrano, Thomas G. Beach, Michael A. Dyer, Richard J. Smeyne, Tudor Moldoveanu, Taosheng Chen, Gang Wu, Stanislav S. Zakharenko, Gang Yu, Junmin Peng

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Abstract

Recent proteome and transcriptome profiling of Alzheimer’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.

Original language	English (US)
Pages (from-to)	923-940
Number of pages	18
Journal	Nature Aging
Volume	2
Issue number	10
DOIs	https://doi.org/10.1038/s43587-022-00290-0
State	Published - Oct 2022

ASJC Scopus subject areas

Geriatrics and Gerontology
Aging
Neuroscience (miscellaneous)

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Chen, P. C., Han, X., Shaw, T. I., Fu, Y., Sun, H., Niu, M., Wang, Z., Jiao, Y., Teubner, B. J. W., Eddins, D., Beloate, L. N., Bai, B., Mertz, J., Li, Y., Cho, J. H., Wang, X., Wu, Z., Liu, D., Poudel, S., ... Peng, J. (2022). Alzheimer’s disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment. Nature Aging, 2(10), 923-940. https://doi.org/10.1038/s43587-022-00290-0

Chen, PC, Han, X, Shaw, TI, Fu, Y, Sun, H, Niu, M, Wang, Z, Jiao, Y, Teubner, BJW, Eddins, D, Beloate, LN, Bai, B, Mertz, J, Li, Y, Cho, JH, Wang, X, Wu, Z, Liu, D, Poudel, S, Yuan, ZF, Mancieri, A, Low, J, Lee, HM, Patton, MH, Earls, LR, Stewart, E, Vogel, P, Hui, Y, Wan, S, Bennett, DA, Serrano, GE, Beach, TG, Dyer, MA, Smeyne, RJ, Moldoveanu, T, Chen, T, Wu, G, Zakharenko, SS, Yu, G & Peng, J 2022, 'Alzheimer’s disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment', Nature Aging, vol. 2, no. 10, pp. 923-940. https://doi.org/10.1038/s43587-022-00290-0

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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 = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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doi = "10.1038/s43587-022-00290-0",

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AU - Chen, Ping Chung

AU - Han, Xian

AU - Shaw, Timothy I.

AU - Fu, Yingxue

AU - Sun, Huan

AU - Niu, Mingming

AU - Wang, Zhen

AU - Jiao, Yun

AU - Teubner, Brett J.W.

AU - Eddins, Donnie

AU - Beloate, Lauren N.

AU - Bai, Bing

AU - Mertz, Joseph

AU - Li, Yuxin

AU - Cho, Ji Hoon

AU - Wang, Xusheng

AU - Wu, Zhiping

AU - Liu, Danting

AU - Poudel, Suresh

AU - Yuan, Zuo Fei

AU - Mancieri, Ariana

AU - Low, Jonathan

AU - Lee, Hyeong Min

AU - Patton, Mary H.

AU - Earls, Laurie R.

AU - Stewart, Elizabeth

AU - Vogel, Peter

AU - Hui, Yawei

AU - Wan, Shibiao

AU - Bennett, David A.

AU - Serrano, Geidy E.

AU - Beach, Thomas G.

AU - Dyer, Michael A.

AU - Smeyne, Richard J.

AU - Moldoveanu, Tudor

AU - Chen, Taosheng

AU - Wu, Gang

AU - Zakharenko, Stanislav S.

AU - Yu, Gang

AU - Peng, Junmin

PY - 2022/10

Y1 - 2022/10

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Alzheimer’s disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment

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