PXD045799

PXD045799 is an original dataset announced via ProteomeXchange.

Title	Target engagement of Tau antibodies induces reversal of proteomic dyshomeostasis in a mouse model of tauopathy
Description	The 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.
HostingRepository	PRIDE
AnnounceDate	2025-05-06
AnnouncementXML	Submission_2025-05-06_12:10:36.517.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD045799
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Mark Graham
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	methionine oxidation with neutral loss of 64 Da; phosphorylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2023-09-28 23:43:26	ID requested
⏵ 1	2025-05-06 12:10:37	announced

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]

submitter keyword: mouse, Alzheimer’s disease, antibody, proteomics, tau, phosphoproteomics, tauopathies

Jürgen Götz
contact affiliation	Queensland Brain Institute, The University of Queensland, St Lucia Campus (Brisbane), QLD 4072, Australia
contact email	j.goetz@uq.edu.au
lab head
Mark Graham
contact affiliation	Children's Medical Research Institute
contact email	mgraham@cmri.org.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD045799
     1. Label: PRIDE project
     2. Name: Target engagement of Tau antibodies induces reversal of proteomic dyshomeostasis in a mouse model of tauopathy