The human OPA1delTTAG mutation induces premature age-related systemic neurodegeneration in mouse
| Autor: | Jing Wang, Valérie Rigau, Guy Bielicki, Chantal Cazevieille, Marie Seveno, Jean-Luc Puel, Pascal Reynier, Naïg Gueguen, Christian P. Hamel, Anne-Laure Mausset-Bonnefont, Jean-Pierre Renou, Philippe Brabet, Benjamin Chaix, Cécile Delettre, Guy Lenaers, Nathalie Boddaert, Claire Angebault, Emmanuelle Sarzi |
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| Přispěvatelé: | Université Montpellier 1 (UM1), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Qualité des Produits Animaux (QuaPA), Institut National de la Recherche Agronomique (INRA), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire Gui de Chauliac (CHU Gui de Chauliac), Association Francaise contre les Myopathies, Retina France, Union Nationale des Aveugles et Deficients Visuels, Ouvrir Les Yeux, European E-RARE program ERMION |
| Rok vydání: | 2012 |
| Předmět: |
Retinal Ganglion Cells
CARDIOLIPIN Pathology Magnetic Resonance Spectroscopy Mitochondrial Diseases Mitochondrion Nervous System GTP Phosphohydrolases Mice FUSION 0302 clinical medicine [SDV.IDA]Life Sciences [q-bio]/Food engineering Mitophagy Sequence Deletion 0303 health sciences Neurodegeneration Age Factors neurodegeneration Aging Premature DEFECTS Magnetic Resonance Imaging respiratory chain complexes ALZHEIMERS-DISEASE DEFICIENCY mitochondria Phenotype OPA1 MUTATIONS mitochondrial fusion Disease Progression medicine.symptom Glycolysis Locomotion Psychoacoustics medicine.medical_specialty Ataxia DOMINANT OPTIC ATROPHY mouse model Mice Transgenic Biology Retinal ganglion Retina Electron Transport Complex IV 03 medical and health sciences Atrophy Physical Conditioning Animal Optic Atrophy Autosomal Dominant Electroretinography Evoked Potentials Auditory Brain Stem Reaction Time medicine Animals Humans [SPI.GPROC]Engineering Sciences [physics]/Chemical and Process Engineering Lactic Acid Muscle Skeletal 030304 developmental biology Aspartic Acid Chi-Square Distribution Membrane Proteins Optic Nerve MITOCHONDRIAL-DNA INSTABILITY IN-VITRO Creatine medicine.disease eye diseases Mice Inbred C57BL MODEL Disease Models Animal Peripheral neuropathy Acoustic Stimulation Electron Transport Chain Complex Proteins Gene Expression Regulation Evoked Potentials Visual Neurology (clinical) Psychomotor Performance 030217 neurology & neurosurgery |
| Zdroj: | Brain-A Journal of Neurology Brain-A Journal of Neurology, Oxford University Press (OUP), 2012, 135, pp.3599-3613. ⟨10.1093/brain/aws303⟩ |
| ISSN: | 1460-2156 0006-8950 |
| DOI: | 10.1093/brain/aws303 |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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