title: 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.
authors.affiliation: Institut des Neurosciences de Montpellier, INSERM U1051, Université Montpellier I et II CHU St Eloi, 80, rue Auguste Fliche, 34091 Montpellier Cedex 5, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Sarzi
authors.forename: Claire
authors.initials: C
authors.lastname: Angebault
authors.forename: Marie
authors.initials: M
authors.lastname: Seveno
authors.forename: Naïg
authors.initials: N
authors.lastname: Gueguen
authors.forename: Benjamin
authors.initials: B
authors.lastname: Chaix
authors.forename: Guy
authors.initials: G
authors.lastname: Bielicki
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Mausset-Bonnefont
authors.forename: Chantal
authors.initials: C
authors.lastname: Cazevieille
authors.forename: Valérie
authors.initials: V
authors.lastname: Rigau
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Renou
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Cécile
authors.initials: C
authors.lastname: Delettre
authors.forename: Philippe
authors.initials: P
authors.lastname: Brabet
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Puel
authors.forename: Christian P
authors.initials: CP
authors.lastname: Hamel
authors.forename: Pascal
authors.initials: P
authors.lastname: Reynier
authors.forename: Guy
authors.initials: G
authors.lastname: Lenaers
mesh_terms: D000161:Acoustic Stimulation; D000367:Age Factors; D019588:Aging, Premature / Q000235:genetics; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D016009:Chi-Square Distribution; D003401:Creatine / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D004596:Electroretinography; D016057:Evoked Potentials, Auditory, Brain Stem / Q000235:genetics; D005074:Evoked Potentials, Visual / Q000235:genetics; D020558:GTP Phosphohydrolases / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008124:Locomotion / Q000235:genetics; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D028361:Mitochondrial Diseases / Q000150:complications / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology / Q000648:ultrastructure; D009420:Nervous System / Q000473:pathology / Q000648:ultrastructure; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology* / Q000534:rehabilitation; D009900:Optic Nerve / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D010641:Phenotype; D010805:Physical Conditioning, Animal; D011571:Psychoacoustics; D011597:Psychomotor Performance / Q000502:physiology; D011930:Reaction Time / Q000235:genetics; D012160:Retina / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D012165:Retinal Ganglion Cells / Q000473:pathology; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: D045222:Electron Transport Chain Complex Proteins; D008565:Membrane Proteins; D001224:Aspartic Acid; D019344:Lactic Acid; C000179:N-acetylaspartate; D003576:Electron Transport Complex IV; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human; D003401:Creatine