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Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau

ABSTRACT: Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau

PROVIDER: PRJNA659243 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12513928_1.fastq.gz	Fastqsanger.gz
	SRR12513928_2.fastq.gz	Fastqsanger.gz
	SRR12513929_1.fastq.gz	Fastqsanger.gz
	SRR12513929_2.fastq.gz	Fastqsanger.gz
	SRR12513930_1.fastq.gz	Fastqsanger.gz

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Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau

Project description:RNA-seq analysis of wild-type, heterozygous, and homozygous mice with p.Asp395Gly mutation in VCP

2021-01-01 | GSE156831 | GEO

Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau.

Project description:Neurodegeneration in Alzheimer's disease (AD) is closely associated with the accumulation of pathologic tau aggregates in the form of neurofibrillary tangles. We found that a p.Asp395Gly mutation in VCP (valosin-containing protein) was associated with dementia characterized neuropathologically by neuronal vacuoles and neurofibrillary tangles. Moreover, VCP appeared to exhibit tau disaggregase activity in vitro, which was impaired by the p.Asp395Gly mutation. Additionally, intracerebral microinjection of pathologic tau led to increased tau aggregates in mice in which p.Asp395Gly VCP mice was knocked in, as compared with injected wild-type mice. These findings suggest that p.Asp395Gly VCP is an autosomal-dominant genetic mutation associated with neurofibrillary degeneration in part owing to reduced tau disaggregation, raising the possibility that VCP may represent a therapeutic target for the treatment of AD.

| S-EPMC7818661 | biostudies-literature

Distinct tau neuropathology and cellular profiles of a APOE3 Christchurch homozygote protected against Autosomal Dominant Alzheimer’s dementia

Project description:We describe in vivo follow-up PET imaging and postmortem findings from an autosomal dominant Alzheimer’s disease (ADAD) PSEN1 E280A carrier who was also homozygous for the APOE3 Christchurch (APOE3ch) variant and was protected against Alzheimer’s symptoms for almost three decades beyond the expected age of onset. We identified a distinct anatomical pattern of tau pathology with atypical accumulation in vivo and unusual postmortem regional distribution characterized by sparing in the frontal cortex and severe pathology in the occipital cortex. The frontal cortex and the hippocampus, less affected than the occipital cortex by tau pathology, contained Related Orphan Receptor B (RORB) positive neurons, homeostatic astrocytes and higher APOE expression. The occipital cortex, the only cortical region showing cerebral amyloid angiopathy (CAA), exhibited a distinctive chronic inflammatory microglial profile and lower APOE expression. Thus, the Christchurch variant impacts the distribution of tau pathology, modulates age at onset, severity, progression, and clinical presentation of ADAD, suggesting possible therapeutic strategies.

2022-08-26 | GSE206744 | GEO

RNAi knock down of VCP in human HeLa cells

Project description:Study of the effects of the VCP knockdown. VCP (p97, yeast cdc48) is a hexameric AAA ATPase involved in various cellular functions including degradation of proteins by the ubiquitin-proteasome system. We examine the consequences of the reduction of VCP levels after RNAi of VCP in HeLa cells. We find ~30 transcripts upregulated in a sequence independent manner. Those transcripts encode proteins involved in endoplasmic reticulum stress, apoptosis, and amino acid starvation.

2006-08-23 | E-MEXP-817 | biostudies-arrayexpress

Proteomic profiling of VCP substrates links VCP to K6-linked ubiquitylation and c-Myc function

Project description:VCP is an evolutionary conserved ubiquitin-dependent ATPase that mediates the degradation of proteins through the ubiquitin-proteasome pathway. Despite the central role of VCP in the regulation of protein homeostasis, identity and nature of its cellular substrates remain poorly defined. Here, we combined chemical inhibition of VCP and quantitative ubiquitin remnant profiling to assess the effect of VCP inhibition on the ubiquitin-modified proteome and to probe the substrate spectrum of VCP in human cells. We demonstrate that inhibition of VCP perturbs cellular ubiquitylation and increases ubiquitylation of a different subset of proteins compared to proteasome inhibition. VCP inhibition globally upregulates K6-linked ubiquitylation that is dependent on the HECT-type ubiquitin E3 ligase HUWE1. We report ~450 putative VCP substrates, many of which function in nuclear processes, including gene expression, DNA repair and cell cycle. Moreover, we identify that VCP regulates the level and activity of the transcription factor c-Myc.

2018-02-08 | GSE107313 | GEO

Distinct tau neuropathology and cellular profiles of a APOE3 Christchurch homozygote protected against Autosomal Dominant Alzheimer’s dementia

Project description:Distinct tau neuropathology and cellular profiles of a APOE3 Christchurch homozygote protected against Autosomal Dominant Alzheimer’s dementia

| PRJNA851960 | ENA

Neuronal VCP loss of function recapitulates FTLD-TDP pathology

Project description:The pathogenic mechanism by which dominant mutations in VCP cause multisystem proteinopathy (MSP), a rare neurodegenerative disease that presents as fronto-temporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), remains unclear. To explore this, we inactivated VCP in murine postnatal forebrain neurons (VCP cKO). VCP cKO mice have cortical brain atrophy, neuronal loss, autophago-lysosomal dysfunction and TDP-43 inclusions resembling FTLD-TDP pathology. Conditional expression of a single disease-associated mutation, VCP-R155C, in a VCP null background similarly recapitulated features of VCP inactivation and FTLD-TDP, suggesting that this MSP mutation is hypomorphic. Comparison of transcriptomic and proteomic datasets from genetically defined patients with FTLD-TDP reveal that progranulin deficiency and VCP insufficiency result in similar profiles. These data identify a loss of VCP-dependent functions as a mediator of FTLD-TDP and reveal an unexpected biochemical similarity with progranulin deficiency.

2021-06-16 | GSE178257 | GEO

The differentiation/retrodifferentiation program of human U937 leukemia cells is accompanied by changes of VCP/p97

Project description:A possible functional role of VCP/p97 during differentiation of U937 cells was addressed by siRNA-targeting of VCP/p97. Functional changes in VCP-siRNA-transfected cells following phorbol ester-induced monocytic differentiation have been examind by DNA microarray analysis. Cells transfected with the non-targeting AllStars negative siRNA (Qiagen) served as a reference. Computed

2010-06-29 | E-GEOD-9821 | biostudies-arrayexpress

ASPSCR1-TFE3 reprograms transcription by organizing enhancers around hexameric VCP [HiChIP]

Project description:ChIPseq experiments identify that ASPSCR1-TFE3 defines active enhancers across the genome and co-distributes with VCP/p97. RNAseq after knock-down of ASPSCR1-TFE3 or VCP, inhibition of VCP, or overexpression of each in alveolar soft part sarcoma cell lines demonstrates their co-dependence. HiChIP defines chromatin conformations that surround ASPSCR1-TFE3 targets and are lost on VCP knock-down.

2023-01-01 | GSE162068 | GEO

ASPSCR1-TFE3 reprograms transcription by organizing enhancers around hexameric VCP [ASPS1 VCP ChIP]

Project description:Aberrant transcription in alveolar soft part sarcoma (ASPS) is orchestrated by the fusion oncoprotein, ASPSCR1-TFE3, product of a gene fusion created by a t(X;17) chromosomal translocation. Here, proteomics of proteins co-immunoprecipitating with ASPSCR1-TFE3 revealed strong enrichment of VCP/p97, an AAA+ ATPase with known segregase function. Positive and negative genetic experiments with ASPSCR1-TFE3 and VCP demonstrated that they function co-dependently for cancer cell proliferation, colony formation, enhancer activation, chromatin conformation, and transcription

2023-01-01 | GSE162727 | GEO

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