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

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.