MassIVE MSV000096377

Partial Public PXD057755

The interactome of tau phosphorylated at T217 in Alzheimers disease human brain tissue

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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. [doi:10.25345/C5MP4W065] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: phospho Tau ; pT217 ; ALzheimers Disease brain ; DatasetType:Proteomics

Contact

Principal Investigators:
(in alphabetical order) 		Beatrix Ueberheide, NYU School of Medicine, USA
Submitting User: Trixi

Publications

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. 2025 May 3;149(1):44. Epub 2025 May 3.

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