PXD079144

PXD079144 is an original dataset announced via ProteomeXchange.

Title	Serine-65 phosphorylated ubiquitin associates with soluble Tau and seeding activity in Alzheimer’s disease
Description	Tau propagation is a key driver of Alzheimer’s disease (AD), yet selective markers of seeding-competent tau remain elusive. Ubiquitin phosphorylated at Serine-65 (pS65-Ub) is a PINK1-derived stress signal that accumulates in AD with elevated tau pathology, but its functional relationship to tau seeding is unknown. Here, using complementary imaging and biochemical approaches, we show that tau is covalently modified by pS65-Ub in AD brain. pS65-Ub modified tau is elevated in AD frontal cortex, enriched in Triton X-100-soluble fractions, and tightly associated with high-molecular-weight, oligomeric, and hyperphosphorylated tau. Importantly, immunodepletion of pS65-Ub from AD brain lysates nearly abolishes tau seeding in biosensor cells, indicating that tau seeding activity is associated with pS65-Ub modified species. Collectively, these findings establish pS65-Ub as a critical and highly specific marker for identifying, isolating, and eliminating pathogenic tau seeds. This strongly supports the development of pS65-Ub–targeted diagnostics and precision therapeutic approaches aimed at the selective clearance of disease-driving tau species, potentially transforming both early detection and intervention strategies for AD. To confirm tau as a pS65-Ub substrate and further characterize the species attached to pS65-Ub, we performed proteomic analyses. We carried out pS65-Ub IP after denaturation of frontal cortex lysates from five AD patients, with matched biotin labeled isotype IgG IPs as negative controls, and subjected the IP eluates to liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis.
HostingRepository	PRIDE
AnnounceDate	2026-09-02
AnnouncementXML	Submission_2026-09-02_14:37:07.188.xml
DigitalObjectIdentifier	https://doi.org/10.6019/PXD079144
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Wolfdieter Springer
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	ubiquitination signature dipeptidyl lysine; phosphorylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2026-06-01 11:54:39	ID requested
⏵ 1	2026-09-02 14:37:07	announced

10.6019/PXD079144;

submitter keyword: tau seeding, phosphorylated ubiquitin,Alzheimer’s disease, pS65-Ub

Wolfdieter Springer
contact affiliation	Neuroscience, Mayo Clinic College of Medicine and Science, Mayo Clinic, Jacksonville, Florida
contact email	springer.wolfdieter@mayo.edu
lab head
Wolfdieter Springer
contact affiliation	Mayo Clinic Jacksonville
contact email	springer.wolfdieter@mayo.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD079144
     1. Label: PRIDE project
     2. Name: Serine-65 phosphorylated ubiquitin associates with soluble Tau and seeding activity in Alzheimer’s disease