PXD057755

PXD057755 is an original dataset announced via ProteomeXchange.

Title	The interactome of tau phosphorylated at T217 in Alzheimers disease human brain tissue
Description	Tau phosphorylation and aggregation are pathological features of Alzheimers disease. Tau phosphorylated at threonine 217 (pT217) and threonine 231 (pT231) are early fluid biomarkers of Alzheimers disease, suggesting early involvement in disease. However, little is known about the specific actions of these types of phosphorylated tau in Alzheimers disease. Here we performed affinity purification mass spectrometry of pT217 and pT231 tau to determine how phosphorylation of specific tau residues alters its interactome in Alzheimers disease post-mortem brain tissue (n=10). These patients were a balanced cohort of APOE e3/e3 and e4/e4 genotypes (n=5 each) to explore how the most significant AD genetic risk factor altered phosphorylated tau interactions. Results were also compared to our previous interactome dataset examining tau phosphorylated at S396/S404 (enriched using the PHF1 antibody) generated using the same cases. pT217 affinity purification mass spectrometry identified 23 interacting proteins (SAINT score > 0.65). pT217 enriched tau had a constrained phosphorylation signature compared to PHF1 enriched tau, but interactors shared significant overlap. The phosphorylation patterns of pT217 enriched tau included lower intensities of phosphorylation at epitopes serine 396 and serine 404 than PHF1 enriched tau, suggesting pT217 tau was at an earlier state of dysregulation. pT217 interacting proteins were most significantly enriched for biological processes involved in protein catabolism, highlighting the CTLH E3 ubiquitin ligase complex as a novel interactor of multiple phosphorylated tau species (5 interacting subunits: WDR26, ARMC8, GID8, RANBP9, MAEA). In APOE e3/e3 cases pT217 significantly interacted with 46 proteins compared to 28 in APOE e4/e4 cases. These interacting proteins were significantly overlapped, with 13 proteins in common (Fishers exact p = 9x10-23). CTLH E3 ubiquitin ligase subunits significantly interacted with phosphorylated tau in both APOE genotypes. pT231 immunoprecipitation failed to sufficiently enrich tau but results are provided in supplementary data. The phosphorylated tau interaction with p62 and the CTLH component WDR26 were validated using co-immunoprecipitation and immunofluorescent microscopy of fixed post-mortem human brain tissue. In conclusion, our results report the interactome of pT217 in human Alzheimers disease brain tissue for the first time and highlight the CTLH complex as a significant novel interactor of multiple types of phosphorylated tau, including those increased early in Alzheimers disease. The mass spectrometric files of this AP-MS experiment are included here.
HostingRepository	MassIVE
AnnounceDate	2025-05-23
AnnouncementXML	Submission_2025-05-23_15:08:14.431.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Beatrix Ueberheide
SpeciesList	scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606;
ModificationList	Oxidation; Phospho
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2024-11-11 09:01:24	ID requested
⏵ 1	2025-05-23 15:08:15	announced

Kavanagh T, Thierry M, Balcomb K, Ponce J, Kanshin E, Tapia-Sealey A, Halliday G, Ueberheide B, Wisniewski T, Drummond E, The interactome of tau phosphorylated at T217 in Alzheimer's disease human brain tissue. Acta Neuropathol, 149(1):44(2025) [pubmed]

submitter keyword: phospho Tau, pT217, ALzheimers Disease brain, DatasetType:Proteomics

Beatrix Ueberheide
contact affiliation	NYU School of Medicine
contact email	beatrix.ueberheide@nyulangone.org
lab head
Beatrix Ueberheide
contact affiliation	NYU School of Medicine
contact email	beatrixueberheide@gmail.com
dataset submitter

MassIVE dataset URI

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