Cell type- and tau lesion-specific accumulation of phospho-Ser65 ubiquitin in primary tauopathies

Topic: Brain proteins, microglia and lab models

Defective mitochondrial quality control is increasingly implicated in tau-mediated neurodegeneration, but how distinct tau lesions in different cell types interact with PINK1-PRKN-mediated mitophagy remains unclear. Phosphorylated ubiquitin at serine 65 (pS65-Ub) is the joint product of PINK1-PRKN signaling. Significant deposition of pS65-Ub has been previously demonstrated in autopsy brains from patients with Lewy body disease, Alzheimer disease, and MAPT mutation-associated frontotemporal lobar degeneration, where increased pS65-Ub signal was particularly strongly associated with early neuronal tau pathology. We here expanded the analyses to 92 postmortem human brains comparing neuropathologically normal controls and cases of primary age-related tauopathy (PART), Pick’s disease (PiD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Using pS65-Ub and pS202-tau immunohistochemistry in selectively vulnerable regions, deep learning-based quantification of tau lesion subtypes, and single-cell co-localization analyses, we found considerable disease-, cell type-, and tau inclusion-specific differences in pS202-tau and pS65-Ub accumulation. Although pS202-tau burden was elevated across all primary tauopathies in their respective vulnerable regions, the extent of pathology and predominant tau inclusion types varied markedly among diseases. pS65-Ub positive cells were most abundant in the hippocampus of PART and PiD but were sparse in the primary motor cortex of PSP and especially in CBD, despite extensive tau pathology. In both PART and PiD, pS65-Ub primarily accumulated in neurons containing tau inclusions, with significantly greater intracellular burden and more frequent large vacuolar structures in PART. The density of pS65-Ub/tau double-positive cells strongly correlated with tau tangle burden in PART but not with Pick body burden in PiD. Together, our findings revealed marked heterogeneity in the distribution, density, intracellular abundance, and morphology of pS65-Ub deposits across affected brain regions in primary tauopathies, highlighting pS65-Ub as a potential marker for differential diagnosis of neuronal tau-associated disorders in tauopathies.

@article{hou2026-2d393b48,
  author  = {Hou, Xu and Powles, Savannah Tiemann and Hompesch, Hannah and Rubiano, Julian and Koga, Shunsuke and Chen, Taylor Hsuan‐Yu and Murray, Melissa Erin and Dickson, Dennis W. and others},
  title   = {{Cell type- and tau lesion-specific accumulation of phospho-Ser65 ubiquitin in primary tauopathies}},
  journal = {Acta Neuropathologica Communications},
  year    = {2026},
  doi     = {10.1186/s40478-026-02426-4},
  url     = {https://doi.org/10.1186/s40478-026-02426-4}
}

Key findings

• Significant deposition of pS65-Ub has been previously demonstrated in autopsy brains from patients with Lewy body disease, Alzheimer disease, and MAPT mutation-associated frontotemporal lobar degeneration, where increased pS65-Ub signal was particularly strongly associated with early neuronal tau pathology.
• Using pS65-Ub and pS202-tau immunohistochemistry in selectively vulnerable regions, deep learning-based quantification of tau lesion subtypes, and single-cell co-localization analyses, we found considerable disease-, cell type-, and tau inclusion-specific differences in pS202-tau and pS65-Ub accumulation.
• In both PART and PiD, pS65-Ub primarily accumulated in neurons containing tau inclusions, with significantly greater intracellular burden and more frequent large vacuolar structures in PART.
• Together, our findings revealed marked heterogeneity in the distribution, density, intracellular abundance, and morphology of pS65-Ub deposits across affected brain regions in primary tauopathies, highlighting pS65-Ub as a potential marker for differential diagnosis of neuronal tau-associated disorders in tauopathies.

Why it matters

In 92 postmortem human brains, the amount of pS65-Ub and pS202-tau varied by disease, cell type and tau inclusion type across several primary tauopathies. This is autopsy research that describes patterns of pathology and does not test any treatment.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1186/s40478-026-02426-4
• Original source →
• Free full text: Acta Neuropathologica Communications →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

Related studies in Disease mechanisms

• Sex-specific and cell-type-specific changes in chaperone-mediated autophagy across tissues during aging Nature aging · 2025-02-05 · usefulness score 46/100
• Temporal transcriptomic changes in the THY-Tau22 mouse model of tauopathy display cell type- and sex-specific differences Acta Neuropathologica Communications · 2025-05-07 · usefulness score 42/100
• Cell type-specific histone acetylation landscape in Alzheimer’s disease reveals a putative role of MITF in microglia bioRxiv · 2026-09-14 · usefulness score 16/100
• Disrupted ubiquitin proteasome system underlying tau accumulation in Alzheimer's disease Neurobiology of aging · 2020-12-08 · usefulness score 41/100
• The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system The American journal of pathology · 2012-08-04 · usefulness score 36/100
• Rapid accumulation of endogenous tau oligomers in a rat model of traumatic brain injury: possible link between traumatic brain injury and sporadic tauopathies The Journal of biological chemistry · 2013-04-30 · usefulness score 36/100

Also tagged “phosphorylated”

732 studies in the library carry the topic tag “phosphorylated”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 732 tagged studies.

• Microglial activation protects against accumulation of tau aggregates in nondemented individuals with underlying Alzheimer's disease pathology Nature aging · 2022-11-28 · usefulness score 60/100 · TREM2 and immune genetics
• Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer's continuum when only subtle changes in Aβ pathology are detected EMBO molecular medicine · 2020-11-10 · usefulness score 55/100 · Tau biomarkers
• Associations between [18F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample Neurology · 2017-12-27 · usefulness score 53/100 · Brain scans and imaging

Similar studies

• Accumulation of pathological tau species and memory loss in a conditional model of tauopathy 2007 · Lewy body dementia
• Phosphorylated Tau in Alzheimer's Disease and Other Tauopathies 2022 · Lewy body dementia
• Comparison of Common and Disease-Specific Post-translational Modifications of Pathological Tau Associated With a Wide Range of Tauopathies 2020 · Disease mechanisms
• Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform 1999 · Lewy body dementia
• The importance of tau phosphorylation for neurodegenerative diseases 2013 · Lewy body dementia
• Molecular pathology and synaptic loss in primary tauopathies: an 18F-AV-1451 and 11C-UCB-J PET study 2022 · Disease mechanisms

More on Disease mechanisms

• A review that covers this ground Mechanisms of Cell-to-Cell Transmission of Pathological Tau: A Review JAMA neurology · 2019-01-01 · usefulness score 41/100
• Newest in this subject Aβ42 oligomers disrupt calcium homeostasis via Piezo1 and induce neurotoxicity in differentiated SH-SY5Y cells Research Square · 2026-10-29 · Preprint — not yet peer-reviewed · usefulness score 16/100
• Newest in this subject Neuronal Hyperactivity Induces Tau Phosphorylation Selectively in Excitatory Pyramidal Neurons Which Contributes to GluA2 Regulation bioRxiv · 2026-10-28 · Preprint — not yet peer-reviewed · usefulness score 16/100

See all studies in Disease mechanisms →