Frontotemporal lobar degeneration (
FTLD) is a clinically, genetically, and neuropathologically heterogeneous group of neurodegenerative syndromes, leading to progressive
cognitive dysfunction and frontal and temporal
atrophy. C9orf72 hexanucleotide repeat expansion (C9-HRE) is the most common genetic cause of
FTLD, but pathogenic mechanisms underlying
FTLD are not fully understood. Here, we compared cellular features and functional properties, especially related to protein degradation pathways and mitochondrial function, of
FTLD patient-derived skin fibroblasts from C9-HRE carriers and non-carriers and healthy donors. Fibroblasts from C9-HRE carriers were found to produce
RNA foci, but no
dipeptide repeat
proteins, and they showed unchanged levels of C9orf72
mRNA transcripts. The main protein degradation pathways, the
ubiquitin-
proteasome system and autophagy, did not show alterations between the fibroblasts from C9-HRE-carrying and non-carrying
FTLD patients and compared to healthy controls. An increase in the number and size of p62-positive puncta was evident in fibroblasts from both C9-HRE carriers and non-carriers. In addition, several parameters of mitochondrial function, namely, basal and maximal respiration and respiration linked to
ATP production, were significantly reduced in the
FTLD patient-derived fibroblasts from both C9-HRE carriers and non-carriers. Our findings suggest that
FTLD patient-derived fibroblasts, regardless of whether they carry the C9-HRE expansion, show unchanged proteasomal and autophagic function, but significantly impaired mitochondrial function and increased accumulation of p62 when compared to control fibroblasts. These findings suggest the possibility of utilizing
FTLD patient-derived fibroblasts as a platform for
biomarker discovery and testing of drugs targeted to specific cellular functions, such as mitochondrial respiration.