Mass spectrometry-based proteomic profiling of human tauopathy brains suggests mitochondria-associated alterations.

Overview

1. Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan
2. Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan
3. Center for Human Brain Resource Initiative (ChBRI), Niigata University, Niigata, Japan
4. Gunma University, Maebashi, Japan
5. Department of Omics and Systems Biology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan

Abstract

Tauopathies are neurodegenerative disorders characterized by intracellular accumulation of abnormal tau encoded by MAPT, yet their molecular mechanisms remain incompletely understood. We aimed to identify proteomic signatures associated with the primary tauopathies corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), as well as the secondary tauopathy Alzheimer’s disease (AD), and to characterize their interaction networks. Total homogenates from the specified cortical region of postmortem brains of AD (n = 4), CBD (n = 4), PSP (n = 4), and control (n = 4) subjects were analyzed by mass spectrometry (MS). Differentially expressed proteins were subjected to functional enrichment and protein–protein interaction (PPI) network analyses. Reproducibility was assessed using JESS-based western blotting (WB), and selected candidates were examined by immunohistochemistry (IHC) and single-nucleus RNA sequencing (snRNA-seq) to evaluate cell-type–specific transcriptomic profiles. In the four-group comparison, 859, 114, 6, and 1 proteins showed PFDR < 0.05, < 0.01, < 0.005, and < 0.001, respectively. Six proteins (AK3, ATP5PD, COX7C, PPA1, PREP, and UQCRC1) with PFDR < 0.005 formed a highly interconnected network enriched for mitochondrial pathways, including oxidative phosphorylation and respiratory electron transport. WB validation showed strong concordance for four proteins (AK3, PREP, PPA1, and ATP5PD). IHC confirmed neuronal expression of PPA1 and PREP and revealed prominent microglial PPA1 immunoreactivity in PSP brains. snRNA-seq provided complementary cell-type–specific transcriptomic alterations. These findings suggest mitochondria-associated molecular changes shared across primary and secondary tauopathies; however, given the exploratory nature of this study, these observations should be interpreted cautiously and considered hypothesis-generating, warranting further investigation.

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Data

Data links

• ncbi.nlm.nih.gov/geo, NCBI; found in “Data availability statement”

Data availability statement

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found at: http://www.proteomexchange.org/, PXD072806; https://repository.jpostdb.org/, JPST004307; https://www.ncbi.nlm.nih.gov/geo/, GSE317746.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 15 authors, 8 keywords, 17 references.

Cite

This paper

Jannah, A. R., Hasegawa, M., Ham, J., Hara, N., Tsukie, T., Obinata, A., Kikuchi, M., Kasuga, K., Yamaguchi, H., Hamasaki, H., Tada, M., Kakita, A., Matsumoto, M., Miyashita, A., & Ikeuchi, T. (2026). Mass spectrometry-based proteomic profiling of human tauopathy brains suggests mitochondria-associated alterations. Frontiers in molecular neuroscience, 19, 1815858. https://doi.org/10.3389/fnmol.2026.1815858

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