Open Close
Reference
Citation
Bayat, V., Thiffault, I., Jaiswal, M., T├ętreault, M., Donti, T., Sasarman, F., Bernard, G., Demers-Lamarche, J., Dicaire, M.J., Mathieu, J., Vanasse, M., Bouchard, J.P., Rioux, M.F., Lourenco, C.M., Li, Z., Haueter, C., Shoubridge, E.A., Graham, B.H., Brais, B., Bellen, H.J. (2012). Mutations in the Mitochondrial Methionyl-tRNA Synthetase Cause a Neurodegenerative Phenotype in Flies and a Recessive Ataxia (ARSAL) in Humans.  PLoS Biol. 10(3): e1001288.
FlyBase ID
FBrf0217845
Publication Type
Research paper
Abstract

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.

PubMed ID
PubMed Central ID
PMC3308940 (PMC) (EuropePMC)
Associated Information
Comments
Associated Files
Other Information
Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    PLoS Biol.
    Title
    PLoS Biology
    Publication Year
    2003-
    ISBN/ISSN
    1545-7885 1544-9173
    Data From Reference