Frontotemporal dementia associated CHCHD10V57E mutation aggravates tau pathology via disrupting the CHCHD10-Rab7A-TBC1D15 complex

Topic: Brain proteins, microglia and lab models

Abstract Frontotemporal dementia (FTD), a neurodegenerative disorder characterized by early-onset cognitive decline, includes two major pathologic types: FTD-Tau and FTD-TDP. Coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) encodes a mitochondrial protein, and the CHCHD10 V57E variant is a novel mutation clinically identified in FTD patients. The role of CHCHD10 mutants in the pathogenesis of FTD-TDP has been largely reported. However, whether CHCHD10 variants impact the FTD-tau pathology or tau-mediated neurodegeneration is not clear. Here, we generated CHCHD10 V57E mutant Drosophila and mammalian cell culture models on a human R406W tau or 0N4R tau expressing background. We discovered that the CHCHD10 V57E mutation aggravates retinal degeneration, climbing defects, and short lifespan in tau R406W Drosophila . Additionally, the CHCHD10 V57E mutation promotes synaptic integrity defects, increases secretion of total and phosphorylated tau, and induces cytotoxicity in tau-overexpressing mammalian cell culture models. Further studies indicated that localization of the endogenous and wild-type CHCHD10, as well as the V57E mutant, includes the mitochondrial inner and outer membranes. Furthermore, we showed that phosphorylated tau accumulates within the endo-lysosomal system of the CHCHD10 V57E -expressing flies and mammalian cells. Depletion of endosomal protein Rab7A partially attenuates neurodegeneration, reduces total and phosphorylated tau secretion, and diminishes cytotoxicity in tauopathy models expressing CHCHD10 V57E . Mechanistically, we presented evidence that the CHCHD10-Rab7A-TBC1D15 complex maintains Rab7A in an inactive state. By contrast, CHCHD10 V57E expression dissociates the protein complex, resulting in Rab7A activation. Taken together, our study proposes a model whereby the FTD-associated CHCHD10 V57E mutation modulates the activation process of Rab7A, resulting in promoting the development of tau pathologies.

Key findings

• Further studies indicated that localization of the endogenous and wild-type CHCHD10, as well as the V57E mutant, includes the mitochondrial inner and outer membranes.
• Furthermore, we showed that phosphorylated tau accumulates within the endo-lysosomal system of the CHCHD10 V57E -expressing flies and mammalian cells.
• Taken together, our study proposes a model whereby the FTD-associated CHCHD10 V57E mutation modulates the activation process of Rab7A, resulting in promoting the development of tau pathologies.

Why it matters

In fruit fly and cell culture models, the frontotemporal dementia-associated CHCHD10 V57E mutation worsened tau-related degeneration and caused phosphorylated tau to build up in the endo-lysosomal system. These are laboratory models only, so it is too early to say whether this mechanism can be targeted to treat people.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/s41419-026-08983-9
• PubMed: 42321182
• Original source →
• Free full text: Cell Death and Disease →

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

@article{sheng2026-42321182,
  author  = {Sheng, Jie and Yan, Jing and Xu, Yan and Xu, Xingyu and Zhang, Xuemei and Wang, A G and Liu, Buhui and Ma, Jun and others},
  title   = {{Frontotemporal dementia associated CHCHD10V57E mutation aggravates tau pathology via disrupting the CHCHD10-Rab7A-TBC1D15 complex}},
  journal = {Cell Death and Disease},
  year    = {2026},
  doi     = {10.1038/s41419-026-08983-9},
  pmid    = {42321182},
  url     = {https://doi.org/10.1038/s41419-026-08983-9}
}

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