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PXD045799

PXD045799 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleTarget engagement of Tau antibodies induces reversal of proteomic dyshomeostasis in a mouse model of tauopathy
DescriptionThe microtubule-associated protein Tau is a driver of neuronal dysfunction in Alzheimer’s disease and numerous other tauopathies. In this process, Tau initially undergoes subtle changes to its abundance, subcellular localization and a vast array of post-translational modifications, including phosphorylation, that progressively result in the protein’s aggregation and dysregulation of multiple Tau-dependent cellular processes. Given the various loss- and gain-of-functions of Tau in disease and the brain-wide changes in the proteome that characterize tauopathies, we asked targeting Tau would restore the proteomic dyshomeostasis observed in disease. To this end, we generated a novel pan-Tau antibody, RNJ1, that preferentially binds human Tau and neutralizes proteopathic seeding activity in multiple cell-lines, and benchmarked it against a clinically tested pan-Tau antibody, HJ8.5 (murine version of tilavonemab). We next evaluated both antibodies, alone and in combination, in the K3 mouse model of tauopathy, showing reduced Tau pathology and improved neuronal functions, without obtaining synergistic effects for the combination treatment. Quantitative proteomics revealed deregulation of metabolic and microtubule-associated proteins in K3 compared to wild-type brain, strengthening previously reported findings of functional defects in multiple tauopathy models. Importantly, both treatments, in particular RNJ1, reversed protein and phospho-protein dyshomeostasis for both increased and decreased proteins in the K3 brain, shifting levels towards those observed in wild-type mice. Gene set over-representation analysis further confirmed that proteins undergoing restoration are involved in biological pathways affected in K3 mice. Together, our study suggests that a Tau immunotherapy-induced reversal of proteomic dyshomeostasis links target engagement and treatment efficacy.
HostingRepositoryPRIDE
AnnounceDate2025-05-06
AnnouncementXMLSubmission_2025-05-06_12:10:36.517.xml
DigitalObjectIdentifierhttps://dx.doi.org/10.6019/PXD045799
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportSupported dataset by repository
PrimarySubmitterMark Graham
SpeciesList scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationListmethionine oxidation with neutral loss of 64 Da; phosphorylated residue; deamidated residue; iodoacetamide derivatized residue
InstrumentQ Exactive Plus
Dataset History
RevisionDatetimeStatusChangeLog Entry
02023-09-28 23:43:26ID requested
12025-05-06 12:10:37announced
Publication List
10.6019/PXD045799;
10.1093/brain/awae254;
Cruz E, Nisbet RM, Padmanabhan P, van Waardenberg AJ, Graham ME, Nkajja G, Tapaswi S, Connor BJ, Robinson P, G, ö, tz J, Proteostasis as a fundamental principle of Tau immunotherapy. Brain, 148(1):168-184(2025) [pubmed]
Keyword List
submitter keyword: mouse, Alzheimer’s disease, antibody, proteomics, tau, phosphoproteomics, tauopathies
Contact List
Jürgen Götz
contact affiliationQueensland Brain Institute, The University of Queensland, St Lucia Campus (Brisbane), QLD 4072, Australia
contact emailj.goetz@uq.edu.au
lab head
Mark Graham
contact affiliationChildren's Medical Research Institute
contact emailmgraham@cmri.org.au
dataset submitter
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