PXD035141

PXD035141 is an original dataset announced via ProteomeXchange.

Title	Pharmacoproteomics of non-human primate cerebrospinal fluid after BACE inhibition
Description	The protease BACE1 is a major drug target for Alzheimer’s disease, but chronic BACE1 inhibition is associated with non-progressive worsening that may be caused by modulation of unknown physiological BACE1 substrates. To identify in vivo-relevant BACE1 substrates we applied pharmacoproteomics to non-human-primate cerebrospinal fluid (CSF) after acute treatment with BACE inhibitors. Besides SEZ6, the strongest, dose-dependent reduction was observed for the pro-inflammatory cytokine receptor gp130/IL6ST, which we establish as a new in vivo BACE1 substrate. Gp130 was also reduced in human CSF from a clinical trial with a BACE inhibitor and in plasma of BACE1-deficient mice. Mechanistically, we demonstrate that BACE1 directly cleaves gp130, thereby attenuating membrane-bound gp130 and increasing soluble gp130 abundance and controlling gp130 function in neuronal IL-6 signaling and neuronal survival upon growth-factor withdrawal. In conclusion, BACE1 is a new modulator of gp130 function. The BACE1-cleaved, soluble gp130 may serve as a pharmacodynamic BACE1 activity marker to reduce the occurrence of side effects of chronic BACE1 inhibition in humans.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:10:33.312.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Stephan Mueller
SpeciesList	scientific name: Macaca mulatta (Rhesus macaque); NCBI TaxID: 9544;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2022-07-07 00:52:42	ID requested
1	2023-02-23 03:26:32	announced
⏵ 2	2023-11-14 08:10:34	announced	2023-11-14: Updated project metadata.

M, ü, ller SA, Shmueli MD, Feng X, T, ü, shaus J, Schumacher N, Clark R, Smith BE, Chi A, Rose-John S, Kennedy ME, Lichtenthaler SF, The Alzheimer's disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130. Mol Neurodegener, 18(1):13(2023) [pubmed]

submitter keyword: BACE, beta secretase,Cerebrospinal Fluid, Alzheimer's disease, CSF

Stefan F. Lichtenthaler
contact affiliation	DZNE Munich Neuroproteomics Feodor-Lynen-Str. 17 81377 München Germany
contact email	stefan.lichtenthaler@dzne.de
lab head
Stephan Mueller
contact affiliation	DZNE Munich Neuroproteomics
contact email	stephan.mueller@dzne.de
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/2023/02/PXD035141

PRIDE project URI

• PRIDE
  1. PXD035141
     1. Label: PRIDE project
     2. Name: Pharmacoproteomics of non-human primate cerebrospinal fluid after BACE inhibition