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Mutations in the mitochondrial methionyl-tRNA synthetase cause a neurodegenerative phenotype in flies and a recessive ataxia (ARSAL) in humans.

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  • Additional Information
    • Source:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101183755 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1545-7885 (Electronic) Linking ISSN: 15449173 NLM ISO Abbreviation: PLoS Biol Subsets: MEDLINE
    • Publication Information:
      Original Publication: San Francisco, CA : Public Library of Science, [2003]-
    • Subject Terms:
      Ataxia/*genetics ; Drosophila/*physiology ; Drosophila Proteins/*genetics ; Methionine-tRNA Ligase/*genetics ; Mitochondria/*enzymology ; Neurodegenerative Diseases/*genetics; Adolescent ; Adult ; Animals ; Ataxia/metabolism ; Cell Proliferation ; Child ; Child, Preschool ; Drosophila/enzymology ; Drosophila/genetics ; Drosophila Proteins/metabolism ; Electron Transport ; Electroretinography/methods ; Female ; Gene Expression Regulation, Enzymologic ; HEK293 Cells ; Humans ; Leukoencephalopathies/genetics ; Leukoencephalopathies/metabolism ; Longevity ; Male ; Methionine-tRNA Ligase/metabolism ; Middle Aged ; Mitochondria/genetics ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism ; Muscles/metabolism ; Muscles/physiopathology ; Mutation ; Neurodegenerative Diseases/metabolism ; Oxidative Phosphorylation ; Pedigree ; Phenotype ; Photoreceptor Cells/metabolism ; Photoreceptor Cells/pathology ; Reactive Oxygen Species/metabolism ; Retina/metabolism ; Retina/pathology ; Unfolded Protein Response ; Young Adult
    • Abstract:
      Competing Interests: The authors have declared that no competing interests exist.
      An increasing number of genes required for mitochondrial biogenesis, dynamics, or function have been found to be mutated in metabolic disorders and neurological diseases such as Leigh Syndrome. In a forward genetic screen to identify genes required for neuronal function and survival in Drosophila photoreceptor neurons, we have identified mutations in the mitochondrial methionyl-tRNA synthetase, Aats-met, the homologue of human MARS2. The fly mutants exhibit age-dependent degeneration of photoreceptors, shortened lifespan, and reduced cell proliferation in epithelial tissues. We further observed that these mutants display defects in oxidative phosphorylation, increased Reactive Oxygen Species (ROS), and an upregulated mitochondrial Unfolded Protein Response. With the aid of this knowledge, we identified MARS2 to be mutated in Autosomal Recessive Spastic Ataxia with Leukoencephalopathy (ARSAL) patients. We uncovered complex rearrangements in the MARS2 gene in all ARSAL patients. Analysis of patient cells revealed decreased levels of MARS2 protein and a reduced rate of mitochondrial protein synthesis. Patient cells also exhibited reduced Complex I activity, increased ROS, and a slower cell proliferation rate, similar to Drosophila Aats-met mutants.
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    • Grant Information:
      P30 HD024064 United States HD NICHD NIH HHS; T32 HD055200 United States HD NICHD NIH HHS; 44202 Canada CAPMC CIHR
    • Accession Number:
      0 (Drosophila Proteins)
      0 (Mitochondrial Proteins)
      0 (Reactive Oxygen Species)
      EC 6.1.1.10 (Methionine-tRNA Ligase)
    • Publication Date:
      Date Created: 20120327 Date Completed: 20120712 Latest Revision: 20211021
    • Publication Date:
      20250114
    • Accession Number:
      PMC3308940
    • Accession Number:
      10.1371/journal.pbio.1001288
    • Accession Number:
      22448145