Region-resolved multi-layer proteomics reveals proteostasis-centered post-translational remodeling during mouse brain aging
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Updated: Nov 5, 2026
Isolation of Intermediate Filament Proteins from Multiple Mouse Tissues to Study Aging-associated Post-translational Modifications
Published on: May 18, 2017
Qi Xiao1, Weirong Xiang2, Fei Song2
1College of Life Sciences, Zhejiang University, Hangzhou, China; Affiliated Hangzhou First People's Hospital, State Key Laboratory of Medical Proteomics, School of Medicine, School of Future Biomedicine, Westlake University, Hangzhou, Zhejiang Province, China; Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang Province, China; Research Center for Industries of the Future, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province, China.
Abstract:
Brain aging is a spatially heterogeneous and multi-layered process, yet how protein abundance and post-translational modifications (PTMs) are coordinated across brain regions and over time remains incompletely understood. Here, we present a brain-region-resolved, multi-layer proteomics atlas of mouse brain aging, integrating the proteome, phosphoproteome, acetylome, and ubiquitinome across 11 anatomical regions and five time points spanning from young adulthood to senescence. Using dia-PASEF with PTM-optimized acquisition, we quantified 11,460 proteins with 29,225 phosphorylation sites, 5345 acetylation sites, and 5197 ubiquitination sites across 628 injections, enabling systematic analysis of age-associated molecular trajectories. We find that aging patterns are highly region-specific at both the protein and PTM levels, and the pons emerges as a region with marked phosphorylation-level alterations in aging-related signaling pathways. Notably, we uncover a proteostasis-centered regulatory axis in the aging hippocampus, where reduced ubiquitination and increased acetylation converge on Tau, potentially impairing its degradation. Using a telomerase-deficient mouse model (Tert KO), we show that telomere dysfunction perturbs aging-associated molecular trajectories and induces a divergent proteostasis and stress-response state distinct from physiological brain aging. Together, our study provides a spatiotemporal multi-layer proteomics resource of brain aging and reveals a proteostasis-centered landscape of post-translational remodeling associated with region-specific vulnerability and Tau dysregulation.
