title: Neuroglobin gene therapy prevents optic atrophy and preserves durably visual function in Harlequin mice.
abstract: Neuroglobin (NGB) is considered as an endogenous neuroprotective molecule against stroke, since the protein alleviates the adverse effects of hypoxic and ischemic insults. We previously demonstrated the functional link between NGB and mitochondria since it is required for respiratory chain function. Thus, here, we evaluated the relevance of this effect in the Harlequin (Hq) mouse strain, which exhibits retinal ganglion cell (RGC) loss and optic atrophy due to a respiratory chain complex I (CI) defect. A twofold decrease of NGB amounts was observed in Hq retinas. We constructed a recombinant adeno-associated virus which combines to the mouse NGB open reading frame, its 5' and 3'UTR, for guarantying mRNA stability and translation capacity. The vector was administrated intravitreally to Hq mice and NGB expression was stable for up to 7 months without negative effect on retinal architecture or function. On the contrary, RGCs and their axons were substantially preserved from degeneration; consequently, CI activity in optic nerves was protected conferring improvements in vision. Hence, we established that NGB prevents respiratory chain impairment, therefore, protecting visual function otherwise compromised by mitochondrial energetic failure.
authors.affiliation: INSERM, U968, Paris, France; Sorbonne Universités, UPMC Univ Paris, Institut de la Vision, Paris, France; Centre national de la recherche scientifique, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Lechauve
authors.affiliation: INSERM, U968, Paris, France; Sorbonne Universités, UPMC Univ Paris, Institut de la Vision, Paris, France; Centre national de la recherche scientifique, Paris, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Augustin
authors.affiliation: INSERM, U968, Paris, France; Sorbonne Universités, UPMC Univ Paris, Institut de la Vision, Paris, France; Centre national de la recherche scientifique, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Cwerman-Thibault
authors.affiliation: INSERM, U968, Paris, France; Sorbonne Universités, UPMC Univ Paris, Institut de la Vision, Paris, France; Centre national de la recherche scientifique, Paris, France.
authors.forename: Élodie
authors.initials: É
authors.lastname: Reboussin
authors.affiliation: INSERM, U968, Paris, France; Sorbonne Universités, UPMC Univ Paris, Institut de la Vision, Paris, France; Centre national de la recherche scientifique, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Roussel
authors.affiliation: INSERM U705, CNRS UMR 8206, Université Paris Descartes, Sorbonne Paris Cité, Université Paris Diderot, Faculté de Pharmacie, Paris, France.
authors.forename: René
authors.initials: R
authors.lastname: Lai-Kuen
authors.affiliation: INSERM U705, CNRS UMR 8206, Université Paris Descartes, Sorbonne Paris Cité, Université Paris Diderot, Faculté de Pharmacie, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Saubamea
authors.affiliation: INSERM, U968, Paris, France; Sorbonne Universités, UPMC Univ Paris, Institut de la Vision, Paris, France; Centre national de la recherche scientifique, Paris, France.
authors.forename: José-Alain
authors.initials: JA
authors.lastname: Sahel
authors.affiliation: Sanofi Fovea - Ophthalmology, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Debeir
authors.affiliation: INSERM, U968, Paris, France; Sorbonne Universités, UPMC Univ Paris, Institut de la Vision, Paris, France; Centre national de la recherche scientifique, Paris, France. Electronic address: marisol.corral@inserm.fr.
authors.forename: Marisol
authors.initials: M
authors.lastname: Corral-Debrinski
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000172:deficiency*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D005911:Gliosis / Q000473:pathology / Q000517:prevention & control; D005914:Globins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D000078787:Neuroglobin; D009896:Optic Atrophy / Q000235:genetics / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy*; D012165:Retinal Ganglion Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: D009419:Nerve Tissue Proteins; D000078787:Neuroglobin; D005914:Globins; D042967:Electron Transport Complex I