PXD026685

PXD026685 is an original dataset announced via ProteomeXchange.

Title	VCP loss of function in neurons recapitulates FTLD-TDP pathology
Description	Dominant mutations in unrelated genes cause fronto-temporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and include VCP, which is associated with multisystem proteinopathy (MSP). Conditional inactivation of VCP in postnatal forebrain neurons (VCP cKO) caused cortical brain atrophy, neuronal loss, autophago-lysosomal dysfunction, TDP-43 inclusions and hyperactivity. Quantitative proteomics and single nuclei RNA sequencing on VCP cKO brains identified synaptogenesis and the unfolded protein response as the most decreased and increased pathways respectively. Conditional expression of a single MSP disease mutation, VCP-R155C, in cortical neurons similarly recapitulated features of VCP inactivation and FTLD-TDP. Comparison of transcriptomic and proteomic datasets from genetically defined FTD patients revealed that profiles from GRN carriers were similar to VCP insufficiency. These data support a deficiency in VCP dependent functions as the pathogenic mechanism of FTLD-TDP and reveal an unexpected pathogenic similarity with progranulin deficiency. Enhancing VCP function may be therapeutic in MSP and related forms of FTLD-TDP.
HostingRepository	PRIDE
AnnounceDate	2021-08-06
AnnouncementXML	Submission_2021-08-06_02:13:03.702.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD026685
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Shan Li
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2021-06-14 05:35:22	ID requested
⏵ 1	2021-08-06 02:13:04	announced

Wani A, Zhu J, Ulrich JD, Eteleeb A, Sauerbeck AD, Reitz SJ, Arhzaouy K, Ikenaga C, Yuede CM, Pittman SK, Wang F, Li S, Benitez BA, Cruchaga C, Kummer TT, Harari O, Chou TF, Schr, ö, der R, Clemen CS, Weihl CC, Neuronal VCP loss of function recapitulates FTLD-TDP pathology. Cell Rep, 36(3):109399(2021) [pubmed]

ProteomeXchange project tag: Biology/Disease-Driven Human Proteome Project (B/D-HPP), Human Proteome Project

submitter keyword: VCP/p97, transcriptomic, proteomic, fronto-temporal lobar degeneration

Tsui-Fen Chou
contact affiliation	BBE, Caltech
contact email	tfchou@caltech.edu
lab head
Shan Li
contact affiliation	Caltech
contact email	lflshan@caltech.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2021/08/PXD026685

PRIDE project URI

• PRIDE
  1. PXD026685
     1. Label: PRIDE project
     2. Name: VCP loss of function in neurons recapitulates FTLD-TDP pathology