New Opa1 Mouse Model: From Dominant Optic Atrophy To DOA "Plus" Phenotype

Abstract

Purpose: : Dominant Optic Atrophy (DOA) is an inherited mitochondrial disease mainly caused by mutations in the OPA1 gene, encoding a mitochondrial dynamin involved in membrane dynamics 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.

Methods: : We generated a new Opa1 mouse model carrying the c.2708delTTAG mutation (Opa1^+/Δ58), the most frequent mutation found in patients with DOA. 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

Results: : From the age of 9 months, Opa1^+/Δ58 mice present altered visual function. We 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 affected in both tissues. We observed myopathic COX negative and Ragged Red Fibres in Opa1^+/Δ58 mice as well as significant muscular weakness but no mtDNA instability. MRI analysis revealed cerebral abnormalities in mutant mice

Conclusions: : Here we described a mouse model of DOA "plus" phenotype. We show that a mitochondrial RC primary defect precedes visual and neuromuscular failures. Our findings provide the evidence that mtDNA deletions are not responsible for the pathophysiology of DOA. For the first time in a DOA mouse model we show central and peripheral nervous system impairments. Opa1^+/Δ58 mouse provides a good model of DOA and a noticeable tool to further understand syndromic mitochondrial pathologies

Keywords: neuro-ophthalmology: optic nerve • mitochondria • metabolism