PXD056703

PXD056703 is an original dataset announced via ProteomeXchange.

Title	Identification of a Potent Tau-Aggregate Clearing Compound Using Chemoproteomic-Integrated Phenotypic Screening (Enrichment)
Description	Tauopathies are characterized by the formation of tau protein-based neurofibrillary tangles which impede neuronal function and contribute to the pathology of highly prevalent neurodegenerative disorders such as Alzheimer’s and Pick’s diseases. Despite the impact of these diseases, the underlying biology is poorly understood. Current therapeutic efforts to reduce and remove tau aggregates target a variety of cellular mechanisms including altering tau phosphorylation through kinase inhibition, stimulating autophagy and upregulating protein quality control mechanisms such as the endoplasmic reticulum associated protein degradation pathway (ERAD), however these efforts have not thus far resulted in effective therapeutic interventions. Here, we sought to identify new targets and mechanisms that might be exploited to address tauopathies, through a chemoproteomic-integrated phenotypic screen using a cellular model of tau-aggregate clearance. An optimized analogue derived from this effort induced tau aggregate clearance in both SH-SY5Y and iPSC-derived human neuron models of hTauP301L aggregation at nanomolar concentrations and led to the activation of the ERAD pathway. Chemoproteomic studies revealed interactions with several resident endoplasmic reticulum proteins containing thioredoxin domains whose activities are involved in the ERAD pathway and protein quality control. Genetic knockdown of one of these targets, protein disulfide isomerase 1 (P4HB), was found to recapitulate the tau aggregate-clearance phenotype, indicating that modulation of this protein may be of therapeutic benefit for tauopathies.
HostingRepository	PRIDE
AnnounceDate	2025-09-05
AnnouncementXML	Submission_2025-09-04_16:30:09.765.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Louis Conway
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-10 15:52:52	ID requested
⏵ 1	2025-09-04 16:30:10	announced

Dataset with its publication pending

submitter keyword: fragment,tauopathy, screening, chemoproteomics, photoactivation

Christopher G Parker
contact affiliation	Professor, Department of Chemistry, The Scripps Research Institute
contact email	cparker@scripps.edu
lab head
Louis Conway
contact affiliation	Scripps Research
contact email	lconway@scripps.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/2025/09/PXD056703

PRIDE project URI

• PRIDE
  1. PXD056703
     1. Label: PRIDE project
     2. Name: Identification of a Potent Tau-Aggregate Clearing Compound Using Chemoproteomic-Integrated Phenotypic Screening (Enrichment)