Analysis of molecular mechanism underlying cell death induced by an ALS/FTD-causative gene CHCHD10

Amyotrophic Lateral Sclerosis (ALS) is a motor neuron-specific degenerative disease, and frontotemporal dementia (FTD) is another neurodegenerative disease that causes atrophy of the frontal and temporal lobes. There are pathological and genetical overlap between ALS and FTD regarding their causative genes and the presence of ubiquitin- and TDP-43-positive inclusion bodies. However, the pathogenesis of ALS and FTD remains insufficiently characterized. CHCHD10 (C10), a familial ALS/FTD-causative gene, is expressed in mitochondria and is thought to be involved in the regulation of mitochondrial functions, although the mechanism underlying the C10 mutation-mediated onset of ALS/FTLD remains unknown. In this study, we generated C10-expressing adenoviruses to unravel the mechanism underlying cell death caused by C10 mutations. The results showed that overexpression of wild-type C10 or a C10 mutant induced cell death in parallel with increase in the transcription factor C/EBP homologous protein (CHOP) expression, the indicator of mitochondrial unfolded protein response. Importantly, the overexpression of the C10 mutant caused higher-level cell death and expression of CHOP than wild-type C10. These results suggest that the familial ALS/FTLD-linked mutation of C10 enhances motor neuron toxicity possibly by exaggerated mitochondrial stress.