March 24, 2012
Collaboration Rapidly Connects Fly Gene Discovery To Human Disease
A collaboration by an international consortium of researchers led by scientists at Baylor College of Medicine and the Montreal Neurological Institute of McGill University have linked the discovery of a mutation in a mitochondrial gene in fruit flies that causes the loss of neurologic function (a neurodegenerative set of characteristics or phenotype) and a progressive recessively inherited ataxia or neurodegenerative disorder in humans.
A report in the online, open access journal PLoS Biology describes the forward genetic screen performed by the team of Dr. Hugo Bellen, director of the BCM Program in Developmental Biology and professor of molecular and human genetics. The screen indentified mutations in the fruit fly mitochondrial methionyl-tRNA synthetase o(Aats-met) gene that lead to degeneration of photoreceptors in the eye, shortened life span and other problems, including reductions in cell proliferation.Bellen is also a Howard Hughes Medical Institute Investigator, and a member of the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital.
Mitochondria are the power plants of the cell, and defects in mitochondrial genes are associated with metabolic and neurological disorders. Mitochondria have their own mechanism for producing proteins, separate from the protein-producing machinery of the cell.
Dr. Vafa Bayat, a student in the Graduate Program in Developmental Biology and the Medical Scientist (M.D./Ph.D.) Training Program, identified the mutant gene and searched the literature for neurological disorders that mapped to the genomic region containing the human form (homologue) of this gene, MARS2.
One such disease, Autosomal Recessive Spastic Ataxia with frequent Leukoencephalopathy (ARSAL), mapped to this region of the genome. (Ataxias are progressive neurodegenerative diseases that cause coordination problems that lead to modified gait and speech as well as other problems.)
Subsequently, Bellen, Bayat and the laboratory established a collaboration with a Canadian group, led by Dr. Bernard Brais, who had described and mapped the disease. Brais is co-director with Dr. Eric Shoubridge of the Montreal Neurological Institute's neuromuscular group. His former graduate student, Dr. Isabelle Thiffault, led the work to identify the disease gene and characterize the nature of the human mutations.
The Montreal team identified complex rearrangements of the genetic material in the MARS2 gene, which resulted in reduced levels of the MARS2 protein, reduced protein synthesis by the mitochondria and impaired mitochondrial function in cells derived from patients with the disorder. As with the Drosophila mutants, the patients' cells also exhibited increased levels of reactive oxygen species, which can damage cells and genetic material, and slow cell proliferation.
The complex rearrangement of the gene may have occurred because the gene is surrounded by repetitive DNA elements.
"It's a hotspot for problems, as previously shown by Dr. Jim Lupski at BCM," said Bellen.
Collaborating with Dr. Brett Graham, assistant professor of molecular and human genetics at BCM, the authors found that the mutant flies have defects in their mitochondrial respiratory chain. As the powerhouses of the cell, the mitochondria are responsible for the production of adenosine triphosphate (ATP), the main energy source for the cell. The respiratory chain converts the energy released from the breakdown of sugars, proteins, and fats in the presence of oxygen into energy in the form ATP. If the respiratory chain complexes are defective, the cell cannot make enough energy to accomplish its task. When that happens, increased production of reactive oxygen species results.
"We found the same defect in the mitochondrial respiratory chains in the human cells, which produced a lot of reactive oxygen species," said Bayat. "When we feed the fly larvae antioxidants, they suppress the degenerative phenotypes in flies."
In other words, the antioxidants can reduce the negative characteristics associated with the mutant gene.
"While the discovery of mutations in fly genes has been linked to human disease before, it has often taken many years to decades to accomplish this," said Bellen. "This was a relatively quick process. In summary, we have shown that you can use flies to identify fly mutants with neurodegenerative phenotypes and that these mutants can assist in the identification of human disease genes."
Others who took part in this work include Manish Jaiswal, Martine TÃ©treault, GeneviÃ¨ve Bernard, Julie Demers-Lamarche and Marie-JosÃ©e Dicaire of the Neurogenetics Laboratory in Montreal, Taraka Donti and Zhihong Li of BCM, Florin Sasarman and Eric A. Shoubridge of the Department of Human Genetics at MNI-McGill University in Montreal, Jean Mathieu of Clinique des maladies neuromusculaires, CSSS de JonquiÃ¨re, Saguenay, Quebec; Michel Vanasse of Clinique des maladies neuromusculaires, CHU Sainte-Justine, MontrÃ©al; Jean-Pierre Bouchard of Service de neurologie, CHA-HÃ´pital de l'Enfant-JÃ©sus, UniversitÃ© Laval, Quebec; Marie-France Rioux of Service de neurologie, Centre hospitalier de l'UniversitÃ© de Sherbrooke in Quebec; Charles M. Lourenco of the Department of Medical Genetics at the University of Sao Paulo in Brazil, and Claire Haueter of the Howard Hughes Medical Institute in Houston.
Funding for this work was provided by the HHMI and a National Institute of Child Health and Human Development training grant to the Program in Developmental Biology, the Canadian Institute of Health Research and the Association Canadienne des Ataxies Familiales (ACAF).
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