The molecular mechanisms of OPA1-mediated optic atrophy in Drosophila model and prospects for antioxidant treatment

PLoS Genet. 2008 Jan;4(1):e6. doi: 10.1371/journal.pgen.0040006.

Abstract

Mutations in optic atrophy 1 (OPA1), a nuclear gene encoding a mitochondrial protein, is the most common cause for autosomal dominant optic atrophy (DOA). The condition is characterized by gradual loss of vision, color vision defects, and temporal optic pallor. To understand the molecular mechanism by which OPA1 mutations cause optic atrophy and to facilitate the development of an effective therapeutic agent for optic atrophies, we analyzed phenotypes in the developing and adult Drosophila eyes produced by mutant dOpa1 (CG8479), a Drosophila ortholog of human OPA1. Heterozygous mutation of dOpa1 by a P-element or transposon insertions causes no discernable eye phenotype, whereas the homozygous mutation results in embryonic lethality. Using powerful Drosophila genetic techniques, we created eye-specific somatic clones. The somatic homozygous mutation of dOpa1 in the eyes caused rough (mispatterning) and glossy (decreased lens and pigment deposition) eye phenotypes in adult flies; this phenotype was reversible by precise excision of the inserted P-element. Furthermore, we show the rough eye phenotype is caused by the loss of hexagonal lattice cells in developing eyes, suggesting an increase in lattice cell apoptosis. In adult flies, the dOpa1 mutation caused an increase in reactive oxygen species (ROS) production as well as mitochondrial fragmentation associated with loss and damage of the cone and pigment cells. We show that superoxide dismutase 1 (SOD1), Vitamin E, and genetically overexpressed human SOD1 (hSOD1) is able to reverse the glossy eye phenotype of dOPA1 mutant large clones, further suggesting that ROS play an important role in cone and pigment cell death. Our results show dOpa1 mutations cause cell loss by two distinct pathogenic pathways. This study provides novel insights into the pathogenesis of optic atrophy and demonstrates the promise of antioxidants as therapeutic agents for this condition.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antioxidants / therapeutic use*
  • DNA Transposable Elements / genetics
  • Disease Models, Animal
  • Drosophila
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Eye / ultrastructure
  • GTP Phosphohydrolases / chemistry
  • GTP Phosphohydrolases / genetics*
  • GTP Phosphohydrolases / metabolism
  • Gene Dosage
  • Genes, Dominant
  • Genes, Insect
  • Genetic Techniques
  • Homozygote
  • Humans
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Molecular Sequence Data
  • Mutagenesis, Insertional
  • Mutation
  • Optic Atrophy, Autosomal Dominant / etiology*
  • Optic Atrophy, Autosomal Dominant / genetics*
  • Optic Atrophy, Autosomal Dominant / pathology
  • Optic Atrophy, Autosomal Dominant / therapy*
  • Penetrance
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
  • Superoxide Dismutase / therapeutic use
  • Vitamin E / therapeutic use

Substances

  • Antioxidants
  • DNA Transposable Elements
  • Drosophila Proteins
  • Membrane Proteins
  • OPA1 protein, Drosophila
  • Vitamin E
  • Superoxide Dismutase
  • GTP Phosphohydrolases
  • OPA1 protein, human