Alzheimer's disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment.
Publication/Presentation Date
10-1-2022
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.
Volume
2
Issue
10
First Page
923
Last Page
940
ISSN
2662-8465
Published In/Presented At
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., Yuan, Z. F., … 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
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
36636325
Department(s)
Administration and Leadership
Document Type
Article