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Originally published as Genetics Published Articles Ahead of Print on April 15, 2007.
Genetics, Vol. 176, 937-946, June 2007, Copyright © 2007
doi:10.1534/genetics.107.071688
Mutations in Cytochrome c Oxidase Subunit VIa Cause Neurodegeneration and Motor Dysfunction in Drosophila
Wensheng Liu*,1,
Radhakrishnan Gnanasambandam
,
Jeffery Benjamin,
Gunisha Kaur*,2,
Patricia B. Getman*,
Alan J. Siegel,
Randall D. Shortridge and
Satpal Singh*,3
* Department of Pharmacology and Toxicology, State University of New York, Buffalo, New York 14214 and Department of Biological Sciences, State University of New York, Buffalo, New York 14260
3 Corresponding author: Department of Pharmacology and Toxicology, 102 Farber Hall, State University of New York, Buffalo, NY 14214-3000.
E-mail: singhs{at}buffalo.edu
Mitochondrial dysfunction is involved in many neurodegenerative disorders in humans. Here we report mutations in a gene (designated levy) that codes for subunit VIa of cytochrome c oxidase (COX). The mutations were identified by the phenotype of temperature-induced paralysis and showed the additional phenotypes of decreased COX activity, age-dependent bang-induced paralysis, progressive neurodegeneration, and reduced life span. Germ-line transformation using the levy+ gene rescued the mutant flies from all phenotypes including neurodegeneration. The data from levy mutants reveal a COX-mediated pathway in Drosophila, disruption of which leads to mitochondrial encephalomyopathic effects including neurodegeneration, motor dysfunction, and premature death. The data present the first case of a mutation in a nuclear-encoded structural subunit of COX that causes mitochondrial encephalomyopathy rather than lethality, whereas several previous attempts to identify such mutations have not been successful. The levy mutants provide a genetic model to understand the mechanisms underlying COX-mediated mitochondrial encephalomyopathies and to explore possible therapeutic interventions.
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Genetics 2007 176: NP.
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