CHCHD10 S59L/+ mouse model: Behavioral and neuropathological features of frontotemporal dementia

• Published in: Neurobiology of disease 2024-06, Vol.195, p.106498
• Main Authors: Genin, Emmanuelle C, di Borgo, Pauline Pozzo, Lorivel, Thomas, Hugues, Sandrine, Farinelli, Mélissa, Mauri-Crouzet, Alessandra, Lespinasse, Françoise, Godin, Lucas, Paquis-Flucklinger, Véronique, Petit-Paitel, Agnès
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal - physiology; Disease Models, Animal; Frontotemporal Dementia - genetics; Frontotemporal Dementia - pathology; Hippocampus - metabolism; Hippocampus - pathology; Long-Term Potentiation - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism
• ISSN: 1095-953X
• DOI: 10.1016/j.nbd.2024.106498

CHCHD10-related disease causes a spectrum of clinical presentations including mitochondrial myopathy, cardiomyopathy, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We generated a knock-in mouse model bearing the p.Ser59Leu (S59L) CHCHD10 variant. Chchd10 mice have been shown to phenotypically replicate the disorders observed in patients: myopathy with mtDNA instability, cardiomyopathy and typical ALS features (protein aggregation, neuromuscular junction degeneration and spinal motor neuron loss). Here, we conducted a comprehensive behavioral, electrophysiological and neuropathological assessment of Chchd10 mice. These animals show impaired learning and memory capacities with reduced long-term potentiation (LTP) measured at the Perforant Pathway-Dentate Gyrus (PP-DG) synapses. In the hippocampus of Chchd10 mice, neuropathological studies show the involvement of protein aggregates, activation of the integrated stress response (ISR) and neuroinflammation in the degenerative process. These findings contribute to decipher mechanisms associated with CHCHD10 variants linking mitochondrial dysfunction and neuronal death. They also validate the Chchd10 mice as a relevant model for FTD, which can be used for preclinical studies to test new therapeutic strategies for this devastating disease.