title: Apoptosis-inducing factor deficiency induces early mitochondrial degeneration in brain followed by progressive multifocal neuropathology.
abstract: Apoptosis-inducing factor (AIF) deficiency compromises oxidative phosphorylation. Harlequin mice, in which AIF is downregulated, develop a severe mitochondrial complex I (CI) deficiency, suggesting that Harlequin mice may represent a natural model of the most common oxidative phosphorylation disorders. However, the brain phenotype specifically involves the cerebellum, whereas human CI deficiencies often manifest as complex multifocal neuropathologies. To evaluate whether this model can be used as to study CI-deficient disorders, the whole brain of Harlequin mice was investigated during the course of the disease. Neurodegeneration was not restricted to the cerebellum but progressively affected thalamic, striatal, and cortical regions as well. Strong astroglial and microglial activation with extensive vascular proliferation was observed by 4 months of age in thalamic, striatal, and cerebellar nuclei associated with somatosensory-motor pathways. At 2 months of age, degenerating mitochondria were observed in most cells in these structures, even in nondegenerating neurons, a finding that indicates mitochondrial injury is a cause rather than an effect of neuronal cell death. Thus, apoptosis-inducing factor deficiency induces early mitochondrial degeneration, followed by progressive multifocal neuropathology (a phenotype broader than previously described), and resembles some histopathologic features of devastating human neurodegenerative mitochondriopathies associated with CI deficiency.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U676, Paris, France. elghouzzi@rdebre.inserm.fr
authors.forename: Vincent
authors.initials: V
authors.lastname: El Ghouzzi
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Csaba
authors.forename: Paul
authors.initials: P
authors.lastname: Olivier
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lelouvier
authors.forename: Leslie
authors.initials: L
authors.lastname: Schwendimann
authors.forename: Pascal
authors.initials: P
authors.lastname: Dournaud
authors.forename: Catherine
authors.initials: C
authors.lastname: Verney
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
mesh_terms: D000818:Animals; D051033:Apoptosis Inducing Factor / Q000172:deficiency*; D001253:Astrocytes / Q000473:pathology; D001259:Ataxia / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D016923:Cell Death; D018450:Disease Progression; D042967:Electron Transport Complex I / Q000172:deficiency; D005911:Gliosis / Q000209:etiology / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D017628:Microglia / Q000473:pathology; D008928:Mitochondria / Q000473:pathology*; D009410:Nerve Degeneration; D009422:Nervous System Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D009474:Neurons / Q000473:pathology