Alzheimer's Disease-associated U1 SnRNP Splicing Dysfunction Causes Neuronal Hyperexcitability and Cognitive Impairment

Overview

Journal Nat Aging

Specialty Geriatrics

Date 2023 Jan 13

PMID 36636325

Authors

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

Affiliations

Soon will be listed here.

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 (e.g., 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.

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