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

Author(s): 
Bayat, Vafa
Thiffault, Isabelle
Jaiswal, Manish
TÈtreault, Martine
Donti, Taraka
Sasarman, Florin
Bernard, GeneviËve
Demers-Lamarche, Julie
Dicaire, Marie-JosÈe
Mathieu, Jean
Vanasse, Michel
Bouchard, Jean-Pierre
Rioux, Marie-France
Lourenco, Charles M.
Li, Zhihong
Haueter, Claire
Shoubridge, Eric A.
Graham, Brett H.
Brais, Bernard
Bellen, Hugo J.
Item Type: 
Journal Article
Publication Title: 
PLoS biology
Journal Abbreviation: 
PLoS Biol.
Publication Date: 
2012
Publication Year: 
2012
Pages: 
e1001288
Volume: 
10
Issue: 
3
ISSN: 
1545-7885
DOI: 
10.1371/journal.pbio.1001288
Library Catalog: 
NCBI Published Medical (?)
Extra: 
PMID: 22448145 PMCID: PMC3308940

Turabian/Chicago Citation

Vafa Bayat, Isabelle Thiffault, Manish Jaiswal, Martine TÈtreault, Taraka Donti, Florin Sasarman, GeneviËve Bernard, Julie Demers-Lamarche, Marie-JosÈe Dicaire, Jean Mathieu, Michel Vanasse, Jean-Pierre Bouchard, Marie-France Rioux, Charles M. Lourenco, Zhihong Li, Claire Haueter, Eric A. Shoubridge, Brett H. Graham, Bernard Brais and Hugo J. Bellen. 2012. "Mutations in the mitochondrial methionyl-tRNA synthetase cause a neurodegenerative phenotype in flies and a recessive ataxia (ARSAL) in humans." PLoS biology 10: 3: e1001288. 10.1371/journal.pbio.1001288.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1371/journal.pbio.1001288 | issn = 1545-7885 | volume = 10 | pages = e1001288 | last = Bayat | first = Vafa | coauthors = Thiffault, Isabelle, Jaiswal, Manish, TÈtreault, Martine, Donti, Taraka, Sasarman, Florin, Bernard, GeneviËve, Demers-Lamarche, Julie, Dicaire, Marie-JosÈe, Mathieu, Jean, Vanasse, Michel, Bouchard, Jean-Pierre, Rioux, Marie-France, Lourenco, Charles M., Li, Zhihong, Haueter, Claire, Shoubridge, Eric A., Graham, Brett H., Brais, Bernard, Bellen, Hugo J. | title = Mutations in the mitochondrial methionyl-tRNA synthetase cause a neurodegenerative phenotype in flies and a recessive ataxia (ARSAL) in humans | journal = PLoS biology | date = 2012 | pmid = | pmc = }} </ref>