Hippocampal mitophagy alterations in MAPT-associated frontotemporal dementia with parkinsonism

Topic: Brain proteins, microglia and lab models

The enzyme pair PINK1 and PRKN together orchestrates a cytoprotective mitophagy pathway that selectively tags damaged mitochondria with phospho-serine 65 ubiquitin (pS65-Ub) and directs them for autophagic-lysosomal degradation (mitophagy). We previously demonstrated a significant accumulation of pS65-Ub signals in autopsy brains of sporadic Lewy body disease and Alzheimer's disease cases, which strongly correlated with early tau pathology. In this study, we extended our analysis to a series of pathologically confirmed cases of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) harboring different pathogenic mutations in MAPT, the gene encoding tau. We assessed the morphology, levels, and distribution of the mitophagy tag pS65-Ub in several affected brain regions and hippocampal subregions of these cases. While tau pathological burden was similarly increased across all FTDP-17 cases, pS65-Ub immunopositive signals were strongly accumulated in P301L cases and only weakly present in N279K cases. In the hippocampus of both mutation groups, the density of pS65-Ub positive cells was overall the greatest in the dentate gyrus followed by the subiculum, CA1, and CA2/3, with the CA4 showing only minimal presence. Notably, positive cells in the subiculum carried greater numbers and particularly vacuolar pS65-Ub structures, while cells in the dentate gyrus mostly contained fewer and rather granular pS65-Ub inclusions. Single cell analyses revealed differential co-localization of pS65-Ub with mitochondria, autophagosomes, and lysosomes in these two regions. Together, our study demonstrates distinct mitophagy alteration in different FTDP-17 MAPT cases and hint at selective organelle failure in the hippocampal subregions that was associated with the P301L mutation.

Key findings

• We previously demonstrated a significant accumulation of pS65-Ub signals in autopsy brains of sporadic Lewy body disease and Alzheimer's disease cases, which strongly correlated with early tau pathology.
• In the hippocampus of both mutation groups, the density of pS65-Ub positive cells was overall the greatest in the dentate gyrus followed by the subiculum, CA1, and CA2/3, with the CA4 showing only minimal presence.
• Single cell analyses revealed differential co-localization of pS65-Ub with mitochondria, autophagosomes, and lysosomes in these two regions.
• Together, our study demonstrates distinct mitophagy alteration in different FTDP-17 MAPT cases and hint at selective organelle failure in the hippocampal subregions that was associated with the P301L mutation.

Why it matters

In autopsy brain tissue from people with MAPT-associated frontotemporal dementia with parkinsonism, a marker of mitophagy called pS65-Ub accumulated strongly in P301L cases but only weakly in N279K cases, with different patterns across hippocampal regions. This describes disease processes in brain tissue and does not test a treatment.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1186/s40478-025-01955-8
• PubMed: 39994734
• 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).

@article{richardson2025-39994734,
  author  = {Richardson, Tyrique and Hou, Xu and Fiesel, Fabienne C. and Wszołek, Zbigniew K. and Dickson, Dennis W. and Springer, Wolfdieter},
  title   = {{Hippocampal mitophagy alterations in MAPT-associated frontotemporal dementia with parkinsonism}},
  journal = {Acta Neuropathologica Communications},
  year    = {2025},
  doi     = {10.1186/s40478-025-01955-8},
  pmid    = {39994734},
  url     = {https://doi.org/10.1186/s40478-025-01955-8}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Invited review: Frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging Neuropathology and applied neurobiology · 2015-02-01 · usefulness score 62/100 · Lewy body dementia
• Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17 Science (New York, N.Y.) · 1998-12-01 · usefulness score 59/100 · Lewy body dementia
• Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration Cell · 2022-01-20 · usefulness score 58/100 · Lewy body dementia
• Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17 Proceedings of the National Academy of Sciences of the United States of America · 1998-10-01 · usefulness score 51/100 · Lewy body dementia
• Autophagy flux in CA1 neurons of Alzheimer hippocampus: Increased induction overburdens failing lysosomes to propel neuritic dystrophy Autophagy · 2016-11-04 · usefulness score 51/100 · Brain tissue and pathology
• Age- and disease-dependent increase of the mitophagy marker phospho-ubiquitin in normal aging and Lewy body disease Autophagy · 2018-07-28 · usefulness score 50/100 · Digital health tools
• MAPT mutations, tauopathy, and mechanisms of neurodegeneration Laboratory investigation; a journal of technical methods and pathology · 2019-02-11 · usefulness score 50/100 · Lewy body dementia
• Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice The Journal of biological chemistry · 2005-04-14 · usefulness score 49/100 · Lewy body dementia
• Parkinsonism and frontotemporal dementia: the clinical overlap Journal of molecular neuroscience : MN · 2011-09-03 · usefulness score 40/100 · Digital health tools

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• Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements Proceedings of the National Academy of Sciences of the United States of America · 1999-05-01 · usefulness score 51/100

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