Fibroblasts carrying intermediate C9orf72 hexanucleotide repeat expansions from iNPH patients show impaired energy metabolism but no cell pathologies

Abstract

Long C9orf72 hexanucleotide repeat expansions (C9-HRE) are the most common genetic cause of frontotemporal dementia (FTD), a group of neurodegenerative syndromes leading to cognitive dysfunction and frontal and temporal atrophy. FTD is a potential comorbidity of idiopathic normal pressure hydrocephalus (iNPH) and carrying the C9-HRE can modify the age-of-onset in iNPH patients. While intermediate-length C9-HRE (<30 repeats) are often considered non-pathogenic, the exact pathological cutoff is unclear. In this study, we assessed whether fibroblasts from iNPH patients carrying intermediate C9-HRE display C9-HRE-associated pathological hallmarks and changes in cellular function. C9-HRE-associated RNA foci were not detected in the intermediate carriers. The number of p62-positive puncta was significantly increased only in long C9-HRE carrier fibroblasts, in line with p62-positive intracellular inclusions observed in a brain biopsy from the patient. Specific parameters of mitochondrial respiration were significantly reduced in both the long and intermediate C9-HRE carrier fibroblasts. Fibroblasts from the intermediate C9-HRE carriers showed upregulated glycolytic activity, possibly to counteract the reduced mitochondrial respiration, which could not be observed in the long C9-HRE carriers. In conclusion, these data suggest that while the long C9-HRE leads to more severe cellular pathologies than intermediate C9-HRE, the latter might predispose cells to pathological changes.