The human OPA1delTTAG mutation induces premature age-related systemic neurodegeneration in mouse

Abstract

Dominant optic atrophy is a rare inherited optic nerve degeneration caused by mutations in the mitochondrial fusion gene OPA1. Recently, the clinical spectrum of dominant optic atrophy has been extended to frequent syndromic forms, exhibiting various degrees of neurological and muscle impairments frequently found in mitochondrial diseases. Although characterized by a specific loss of retinal ganglion cells, the pathophysiology of dominant optic atrophy is still poorly understood. We generated an Opa1 mouse model carrying the recurrent Opa1(delTTAG) mutation, which is found in 30% of all patients with dominant optic atrophy. We show that this mouse displays a multi-systemic poly-degenerative phenotype, with a presentation associating signs of visual failure, deafness, encephalomyopathy, peripheral neuropathy, ataxia and cardiomyopathy. Moreover, we found premature age-related axonal and myelin degenerations, increased autophagy and mitophagy and mitochondrial supercomplex instability preceding degeneration and cell death. Thus, these results support the concept that Opa1 protects against neuronal degeneration and opens new perspectives for the exploration and the treatment of mitochondrial diseases.

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

“…Typically, uncoupling agents (FCCP or carbonyl cyanide m ‐chlorophenyl hydrazone, CCCP) promote mitochondrial permeabilization, leading to mitochondrial fragmentation and ultimately sequestration of damaged mitochondria by autophagosomes 45. It has been shown that mitochondria carrying deleterious mtDNA mutations can be selectively eliminated through mitophagy, and increased autophagy has recently been documented in RGCs in murine models of DOA 46, 47, 48…”

Neuroradiological findings expand the phenotype of OPA1-related mitochondrial dysfunction

“…Recently, we generated and analyzed an Opa1 mouse model reproducing the most common mutation c.2708delTTAG found in 30% of all ADOA patients and in 5 out of the 22 patients from this cohort [27]. Small animal MRI disclosed that some 50% of Opa1 ± mice had various combinations of cerebellar atrophy, cortical atrophy and lateral and fourth ventricle dilatation.…”

In vivo time-lapse imaging of mitochondria in healthy and diseased peripheral myelin sheath

“…The construction of the Opa1 knock-in mice with the recurrent OPA1 c.2708_2711delTTAG mutation was described in Sarzi et al (2012). Experiments were carried out on 9 weeks old Opa1 +/mut (Opa1 delTTAG ) mice and Opa1 +/+ littermate controls.…”