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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\n                    <jats:italic>CHCHD10<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>V57E<\/jats:italic>\n                    <\/jats:sup>\n                    mutant\n                    <jats:italic>Drosophila<\/jats:italic>\n                    and mammalian cell culture models on a human R406W tau or 0N4R tau expressing background. We discovered that the\n                    <jats:italic>CHCHD10<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>V57E<\/jats:italic>\n                    <\/jats:sup>\n                    mutation aggravates retinal degeneration, climbing defects, and short lifespan in tau\n                    <jats:sup>R406W<\/jats:sup>\n                    <jats:italic>Drosophila<\/jats:italic>\n                    . Additionally, the\n                    <jats:italic>CHCHD10<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>V57E<\/jats:italic>\n                    <\/jats:sup>\n                    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\n                    <jats:italic>CHCHD10<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>V57E<\/jats:italic>\n                    <\/jats:sup>\n                    -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\n                    <jats:italic>CHCHD10<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>V57E<\/jats:italic>\n                    <\/jats:sup>\n                    . Mechanistically, we presented evidence that the CHCHD10-Rab7A-TBC1D15 complex maintains Rab7A in an inactive state. By contrast, CHCHD10\n                    <jats:sup>V57E<\/jats:sup>\n                    expression dissociates the protein complex, resulting in Rab7A activation. Taken together, our study proposes a model whereby the FTD-associated CHCHD10\n                    <jats:sup>V57E<\/jats:sup>\n                    mutation modulates the activation process of Rab7A, resulting in promoting the development of tau pathologies.\n                  <\/jats:p>","DOI":"10.1038\/s41419-026-08983-9","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T19:55:23Z","timestamp":1781898923000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Frontotemporal dementia associated CHCHD10V57E mutation aggravates tau pathology via disrupting the CHCHD10-Rab7A-TBC1D15 complex"],"prefix":"10.1038","volume":"17","author":[{"given":"Jie","family":"Sheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyu","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anqi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Buhui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3932-0530","authenticated-orcid":false,"given":"Xiuying","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8430-0497","authenticated-orcid":false,"given":"Wei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,19]]},"reference":[{"key":"8983_CR1","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1038\/s41582-018-0009-8","volume":"14","author":"S Van Mossevelde","year":"2018","unstructured":"Van Mossevelde S, Engelborghs S, van der Zee J, Van Broeckhoven C. 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