1. Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10S59L/+ mouse
- Author
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Blandine Madji Hounoum, Françoise Lespinasse, Alessandra Mauri-Crouzet, Delphine Bohl, Fanny Mochel, Emmanuelle Génin, Jean-Ehrland Ricci, Aude Chiot, Véronique Paquis-Flucklinger, Charlotte Cochaud, Julien Neveu, Cynthia Lefebvre-Omar, Sandra Lacas-Gervais, Konstantina Fragaki, Stéphanie Bigou, Gaëlle Augé, Christian S. Lobsiger, Séverine Boillée, Sylvie Bannwarth, Baptiste Ropert, CCMA - Centre Commun de Microscopie Appliquée, and Université Nice Côte D'Azur
- Subjects
0301 basic medicine ,[SDV]Life Sciences [q-bio] ,Motor neuron ,Biology ,Mitochondrion ,Neurotransmission ,medicine.disease ,Spinal cord ,Neuromuscular junction ,3. Good health ,Pathology and Forensic Medicine ,Cell biology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Mitochondrial myopathy ,Mitophagy ,medicine ,Neurology (clinical) ,Amyotrophic lateral sclerosis ,030217 neurology & neurosurgery ,ComputingMilieux_MISCELLANEOUS - Abstract
Recently, we provided genetic basis showing that mitochondrial dysfunction can trigger motor neuron degeneration, through identification of CHCHD10 encoding a mitochondrial protein. We reported patients, carrying the p.Ser59Leu heterozygous mutation in CHCHD10, from a large family with a mitochondrial myopathy associated with motor neuron disease (MND). Rapidly, our group and others reported CHCHD10 mutations in amyotrophic lateral sclerosis (ALS), frontotemporal dementia-ALS and other neurodegenerative diseases. Here, we generated knock-in (KI) mice, carrying the p.Ser59Leu mutation, that mimic the mitochondrial myopathy with mtDNA instability displayed by the patients from our original family. Before 14 months of age, all KI mice developed a fatal mitochondrial cardiomyopathy associated with enhanced mitophagy. CHCHD10S59L/+ mice also displayed neuromuscular junction (NMJ) and motor neuron degeneration with hyper-fragmentation of the motor end plate and moderate but significant motor neuron loss in lumbar spinal cord at the end stage of the disease. At this stage, we observed TDP-43 cytoplasmic aggregates in spinal neurons. We also showed that motor neurons differentiated from human iPSC carrying the p.Ser59Leu mutation were much more sensitive to Staurosporine or glutamate-induced caspase activation than control cells. These data confirm that mitochondrial deficiency associated with CHCHD10 mutations can be at the origin of MND. CHCHD10 is highly expressed in the NMJ post-synaptic part. Importantly, the fragmentation of the motor end plate was associated with abnormal CHCHD10 expression that was also observed closed to NMJs which were morphologically normal. Furthermore, we found OXPHOS deficiency in muscle of CHCHD10S59L/+ mice at 3 months of age in the absence of neuron loss in spinal cord. Our data show that the pathological effects of the p.Ser59Leu mutation target muscle prior to NMJ and motor neurons. They likely lead to OXPHOS deficiency, loss of cristae junctions and destabilization of internal membrane structure within mitochondria at motor end plate of NMJ, impairing neurotransmission. These data are in favor with a key role for muscle in MND associated with CHCHD10 mutations.
- Published
- 2019