PXD034712-1

PXD034712 is an original dataset announced via ProteomeXchange.

Title	Compounds activating VCP D1 ATPase enhance both autophagic and proteasomal neurotoxic protein clearance
Description	Enhancing the removal of aggregate-prone toxic proteins is a rational therapeutic strategy for a number of neurodegenerative diseases, especially Huntington’s disease and various spinocerebellar ataxias. Ideally, such approaches should preferentially clear the mutant/misfolded species, while having minimal impact on the stability of wild-type/normally-folded proteins. Furthermore, activation of both ubiquitin-proteasome and autophagy-lysosome routes may be advantageous, as this would allow effective clearance of both monomeric and oligomeric species, the latter which are inaccessible to the proteasome. Here we find that compounds that activate the D1 ATPase activity of VCP/p97 fulfill these requirements. Such effects are seen with small molecule VCP activators like SMER28, which activate autophagosome biogenesis by enhancing interactions of PI3K complex components to increase PI(3)P production, and also accelerate VCP-dependent proteasomal clearance of such substrates. Thus, this mode of VCP activation may be a very attractive target for many neurodegenerative diseases.
HostingRepository	PRIDE
AnnounceDate	2022-07-15
AnnouncementXML	Submission_2022-07-15_14:59:50.367.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Robin Antrobus
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetic acid derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2022-06-20 01:50:49	ID requested
⏵ 1	2022-07-15 14:59:50	announced
2	2023-11-14 08:57:08	announced	2023-11-14: Updated project metadata.

10.1038/S41467-022-31905-0;

submitter keyword: SMER28, Autophagy, VCP, Ubiquitin-proteasome system, Beclin 1, ATPase, Protein Quality Control, Neurodegeneration

David C. Rubinsztein
contact affiliation	Department of Medical Genetics, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, United Kingdom
contact email	dcr1000@cam.ac.uk
lab head
Robin Antrobus
contact affiliation	CIMR medicine
contact email	pra29@cam.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD034712
     1. Label: PRIDE project
     2. Name: Compounds activating VCP D1 ATPase enhance both autophagic and proteasomal neurotoxic protein clearance