Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE196873 | GEO | 2022/08/11

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

Project description: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.

| S-EPMC9833817 | biostudies-literature

Alzheimer’s disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment [N40K neuron RNA-seq]

2022-08-11 | GSE196872 | GEO

Alzheimer’s disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment [N40K mice RNA-seq]

2022-08-11 | GSE196871 | GEO

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

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

| PRJNA807639 | ENA

Alzheimer’s disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment [N40K neuron RNA-seq]

Project description:Alzheimer’s disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment [N40K neuron RNA-seq]

| PRJNA807643 | ENA

Alzheimer’s disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment [N40K mice RNA-seq]

Project description:Alzheimer’s disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment [N40K mice RNA-seq]

| PRJNA807644 | ENA

Neuronal expression of Alzheimer's disease-associated U1-70K cleavage product causes splicing dysfunction and cognitive impairment in mice

Project description:Alzheimer's disease (AD) displays progressive cognitive decline that is associated with protein ß-amyloid and tau aggregation, but the causative mechanisms are not fully understood. Recent proteomics profiling has identified, in sporadic and familial cases, a tangle-like pathology of U1 small nuclear ribonucleoprotein complex (snRNP), containing U1-70K and its N-terminal cleavage product (N40K), with RNA splicing alteration. To determine whether U1 snRNP dysfunction may play a causative role in AD, we generate a transgenic mouse model (N40K-Tg) by neuronal expression of N40K. Deep transcriptomic analysis of N40K-Tg mice was performed to evaluate intron-retaining mRNAs. Tissue was extracted from hippocampus at three month and twelve month comparing N40K-Tg vs WT mice.

2022-08-11 | GSE115177 | GEO

U1 snRNP Alteration and Neuronal Cell Cycle Reentry in Alzheimer Disease.

Project description:The aberrancy of U1 small nuclear ribonucleoprotein (snRNP) complex and RNA splicing has been demonstrated in Alzheimer's disease (AD). Importantly, the U1 proteopathy is AD-specific, widespread and early-occurring, thus providing a very unique clue to the AD pathogenesis. The prominent feature of U1 histopathology is its nuclear depletion and redistribution in the neuronal cytoplasm. According to the preliminary data, the initial U1 cytoplasmic distribution pattern is similar to the subcellular translocation of the spliceosome in cells undergoing mitosis. This implies that the U1 mislocalization might reflect the neuronal cell cycle-reentry (CCR) which has been extensively evidenced in AD brains. The CCR phenomenon explains the major molecular and cellular events in AD brains, such as Tau and amyloid precursor protein (APP) phosphorylation, and the possible neuronal death through mitotic catastrophe (MC). Furthermore, the CCR might be mechanistically linked to inflammation, a critical factor in the AD etiology according to the genetic evidence. Therefore, the discovery of U1 aberrancy might strengthen the involvement of CCR in the AD neuronal degeneration.

| S-EPMC5876301 | biostudies-literature

A novel intra-U1 snRNP cross-regulation mechanism: alternative splicing switch links U1C and U1-70K expression.

Project description:The U1 small nuclear ribonucleoprotein (snRNP)-specific U1C protein participates in 5' splice site recognition and regulation of pre-mRNA splicing. Based on an RNA-Seq analysis in HeLa cells after U1C knockdown, we found a conserved, intra-U1 snRNP cross-regulation that links U1C and U1-70K expression through alternative splicing and U1 snRNP assembly. To investigate the underlying regulatory mechanism, we combined mutational minigene analysis, in vivo splice-site blocking by antisense morpholinos, and in vitro binding experiments. Alternative splicing of U1-70K pre-mRNA creates the normal (exons 7-8) and a non-productive mRNA isoform, whose balance is determined by U1C protein levels. The non-productive isoform is generated through a U1C-dependent alternative 3' splice site, which requires an adjacent cluster of regulatory 5' splice sites and binding of intact U1 snRNPs. As a result of nonsense-mediated decay (NMD) of the non-productive isoform, U1-70K mRNA and protein levels are down-regulated, and U1C incorporation into the U1 snRNP is impaired. U1-70K/U1C-deficient particles are assembled, shifting the alternative splicing balance back towards productive U1-70K splicing, and restoring assembly of intact U1 snRNPs. Taken together, we established a novel feedback regulation that controls U1-70K/U1C homeostasis and ensures correct U1 snRNP assembly and function.

| S-EPMC3798272 | biostudies-literature

Neuronal expression of Alzheimer's disease-associated U1-70K cleavage product causes splicing dysfunction and cognitive impairment in mice

Project description:Neuronal expression of Alzheimer's disease-associated U1-70K cleavage product causes splicing dysfunction and cognitive impairment in mice

| PRJNA474011 | ENA

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data