Résumé :
|
PURPOSEDominant Optic Atrophy (DOA) is an inherited mitochondrial disease mainly caused by mutations in the OPA1 gene, encoding a dynamin-related GTPase involved in mitochondrial fusion, cristae organization and control of apoptosis. DOA is characterized by visual failure marked by a loss of Retinal Ganglion Cells. Recently, detailed characterization of DOA patients previously thought to be non-syndromic revealed neuromuscular involvements.METHODSWe generated a new Opa1 mouse model carrying the c.2708delTTAG mutation in Exon27 (Opa1+/_58), the most frequent mutation found in patients with DOA (30% of all cases). Firstly, using molecular, electrophysiological and immuno-histological approaches, we characterized the visual function of this mouse. Secondly, we assessed mitochondrial respiratory chain activities in several tissues. Finally, we studied neuromuscular functions using behavioural, histological and molecular experiments as well as MRI technology. RESULTSWe show that from the age of 9 months, Opa1+/_58 animals present altered visual function, with significant delay in the VEP latencies, indicative of impaired optic nerve activity. We also demonstrated a loss of the retinal ganglion cells, hallmark of DOA and demyelination abnormalities in optic nerve. Interestingly, at 5 months before the appearance of the visual defect, we detected a mitochondrial respiratory chain deficiency (RC) in retina and skeletal muscle. Mitochondrial distribution and structure are also early affected in both tissues. We observed myopathic COX negative and Ragged Red Fibres in Opa1+/_58 mice as well as significant muscular weakness. MRI analysis revealed cerebral abnormalities in mutant mice with respect to control littermates.CONCLUSIONSHere we described a mouse model of Dominant Optic Atrophy "plus phenotype". We show that a mitochondrial RC primary defect precedes visual and neuromuscular phenotypes appearance. For the first time in a DOA mouse model, we show central and peripheral nervous system impairments in mutant mice. Opa1+/_58 mouse provides a good model of DOA and a noticeable tool to further understand syndromic mitochondrial pathologies.
|