title: OPA1 deficiency associated with increased autophagy in retinal ganglion cells in a murine model of dominant optic atrophy.
abstract: OBJECTIVE
  To examine retinal ganglion cell (RGC) and axonal abnormalities in an ENU-induced mutant mouse carrying a protein-truncating nonsense mutation in OPA1. Mutations in the OPA1 gene cause autosomal dominant optic atrophy (ADOA) in which loss of RGCs followed by myelin degeneration in the optic nerve leads to progressive decrease in visual acuity.
  
  
  METHODS
  Ultrastructure of the optic nerve was examined in heterozygous mutants and wild-type littermate controls at 6, 9, and 24 months using electron microscopy. The RGC layer was examined at 6 and 24 months.
  
  
  RESULTS
  There was an increase in the number of autophagosomes in the RGC layer in heterozygous mutants compared with wild type at 24 months. Signs of optic nerve degeneration were seen as early as 9 months in Opa1(+/-) mice, with more severe degeneration by 24 months. By 24 months, degeneration of axons was also seen in control mice. Numbers of opaque mitochondria in the Opa1(+/-) mice increased at 6 and 24 months, possibly representing an increase in the density of cristae to fulfill the energy requirements of the axon. In addition, mitochondria with vesiculation of the inner membranes, similar to the mutant mitochondria described in a mouse model of Charcot-Marie-Tooth type 2A, were observed.
  
  
  CONCLUSIONS
  Mutations in OPA1 cause pathologic changes to optic nerve axons that are similar to, but occur earlier than, age-related degeneration. Increased autophagy is likely to result from an increase in abnormal mitochondria and could be one mechanism contributing to RGC loss and subsequent optic atrophy seen in ADOA.
authors.affiliation: Mitochondrial Research Group, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: White
authors.forename: Vanessa J
authors.initials: VJ
authors.lastname: Davies
authors.forename: Vanessa E
authors.initials: VE
authors.lastname: Hogan
authors.forename: Malgorzata J
authors.initials: MJ
authors.lastname: Piechota
authors.forename: Philip P
authors.initials: PP
authors.lastname: Nichols
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Turnbull
authors.forename: Marcela
authors.initials: M
authors.lastname: Votruba
mesh_terms: D000818:Animals; D001343:Autophagy; D001369:Axons / Q000648:ultrastructure*; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005260:Female; D020558:GTP Phosphohydrolases / Q000172:deficiency / Q000235:genetics*; D005838:Genotype; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000648:ultrastructure; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics / Q000473:pathology*; D009900:Optic Nerve / Q000648:ultrastructure*; D016133:Polymerase Chain Reaction; D012165:Retinal Ganglion Cells / Q000648:ultrastructure*
chemical_list: D018389:Codon, Nonsense; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse