Fly study finds FTD-linked CHCHD10 mutation breaks a mitochondria-lysosome brake, worsening tau damage

A Drosophila study published in Cell Death & Disease reports that a mutation in CHCHD10, a gene linked to frontotemporal dementia, releases a brake on an endo-lysosomal protein called Rab7A and makes tau pathology worse in flies. The mechanism differs from other lysosomal pathways already described for FTD, and the findings have not yet been shown in humans.

A mutation called CHCHD10-V57E, found in some patients with frontotemporal dementia (FTD), disrupts a three-protein complex inside cells and worsens tau-related damage in fruit flies, according to a study published in Cell Death & Disease. Researchers built Drosophila and mammalian cell models expressing the mutant CHCHD10 gene alongside a disease-linked form of human tau, R406W, and found that flies carrying both the tau mutation and CHCHD10-V57E had worse eye degeneration, worse climbing ability, and shorter lifespan than flies with the tau mutation alone. The CHCHD10-V57E mutation also increased secretion of tau protein and its phosphorylated form, and caused more cell death in tau-expressing mammalian cell cultures.

CHCHD10 encodes a protein found in mitochondria, the cell's energy-producing structures. The researchers report that CHCHD10, together with two other proteins called Rab7A and TBC1D15, ordinarily forms a complex that keeps Rab7A, a protein that regulates endosomes and lysosomes (the cell's recycling and degradation compartments), in an inactive state. When the mutant CHCHD10-V57E was present, this complex came apart and Rab7A became active. The team also found that phosphorylated tau built up inside the endo-lysosomal system of cells carrying the mutation. When the researchers reduced Rab7A levels in the fly and cell models, eye degeneration, tau secretion, and cell death were partially, not fully, reduced.

The study's authors compared CHCHD10-V57E to a different CHCHD10 mutation, G66V, previously linked to a build-up of a different protein, TDP-43, in FTD. Flies carrying G66V alongside mutant tau showed only mild eye changes similar to flies with normal CHCHD10, while V57E produced markedly worse degeneration, a comparison the researchers say suggests V57E acts through a distinct route from other CHCHD10 mutations already described. CHCHD10 mutations have previously been tied mainly to FTD's TDP-43 pathology and to a related motor neuron disease, ALS; this study is among the first to connect a CHCHD10 mutation to tau pathology specifically, and to describe a mitochondria-to-lysosome trafficking route as separate from the TMEM106B and granulin lysosomal pathway already reported in FTD research.

The findings emerged entirely from genetically engineered fruit flies and cultured mammalian cells expressing extra copies of mutant human tau and CHCHD10, models built to isolate this mechanism rather than to reproduce human disease. No patients, brain tissue, or clinical outcomes were examined in this paper; whether the same complex breaks apart in the brains of people carrying CHCHD10-V57E, or whether that contributes to their symptoms, remains untested.

The researchers say their results point to Rab7A activation as one contributor to tau-related toxicity in models carrying this mutation, alongside other factors, since reducing Rab7A only partly reversed the damage rather than eliminating it.