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<p>Frontotemporal dementia (FTD), a neurodegenerative disorder characterized by early-onset cognitive decline, includes two major pathologic types: FTD-Tau and FTD-TDP. <i>Coiled-coil-helix-coiled-coil-helix domain containing 10</i> (CHCHD10) encodes a mitochondrial protein, and the CHCHD10<sup>V57E</sup> 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 <i>CHCHD10</i><sup><i>V57E</i></sup> mutant <i>Drosophila</i> and mammalian cell culture models on a human R406W tau or 0N4R tau expressing background. We discovered that the <i>CHCHD10</i><sup><i>V57E</i></sup> mutation aggravates retinal degeneration, climbing defects, and short lifespan in tau<sup>R406W</sup> <i>Drosophila</i>. Additionally, the <i>CHCHD10</i><sup><i>V57E</i></sup> 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 <i>CHCHD10</i><sup><i>V57E</i></sup>-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 <i>CHCHD10</i><sup><i>V57E</i></sup>. Mechanistically, we presented evidence that the CHCHD10-Rab7A-TBC1D15 complex maintains Rab7A in an inactive state. By contrast, CHCHD10<sup>V57E</sup> expression dissociates the protein complex, resulting in Rab7A activation. Taken together, our study proposes a model whereby the FTD-associated CHCHD10<sup>V57E</sup> mutation modulates the activation process of Rab7A, resulting in promoting the development of tau pathologies.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月19日

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  • Jie Sheng,
  • Jing Yan,
  • Yan Xu,
  • Xingyu Xu,
  • Xuemei Zhang,
  • Anqi Wang,
  • Buhui Liu,
  • Jun Ma,
  • Xiuying Duan,
  • Heng Zhou,
  • Wei Liu

摘要

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 CHCHD10V57E 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 CHCHD10V57E mutant Drosophila and mammalian cell culture models on a human R406W tau or 0N4R tau expressing background. We discovered that the CHCHD10V57E mutation aggravates retinal degeneration, climbing defects, and short lifespan in tauR406W Drosophila. Additionally, the CHCHD10V57E 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 CHCHD10V57E-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 CHCHD10V57E. Mechanistically, we presented evidence that the CHCHD10-Rab7A-TBC1D15 complex maintains Rab7A in an inactive state. By contrast, CHCHD10V57E expression dissociates the protein complex, resulting in Rab7A activation. Taken together, our study proposes a model whereby the FTD-associated CHCHD10V57E mutation modulates the activation process of Rab7A, resulting in promoting the development of tau pathologies.