Drosophila melanogaster is a good model system to study succinate dehydrogenase (SDH) deficiency disease since there are well characterized mutations in the majority of genes that encode for the Drosophila SDH subunits. Mutations in dSdhA are used as models of Leigh Syndrome in flies, and have comparable neurological consequences to those described in patients. Also, mutations in dSdhB and dSdhC result in increased levels of reactive oxygen species and an early onset of mortality and age-related behavioral decay. Molecular genetic analysis in D. melanogaster provides unique approaches to uncover the basic mechanism of action of potential treatments. In this context, we have preliminary data indicating that SDH activity is increased in the mitochondria of flies that were fed the drug rapamycin. Rapamycin is currently being used in organ transplant patients to prevent rejection. Research using experimental animals also suggests that rapamycin has anti- carcinogenic and pro-longevity characteristics. Based on our observations and the documented effects of rapamycin in this proposal we will test the hypothesis that rapamycin can protect from the pathology induced by SDH deficiency, using D. melanogaster as a genetic model.

Public Health Relevance

Mitochondria are cellular organelles responsible, among other processes, for providing 90% of the energy that cells need. Defects on genes encoding proteins that are critical for mitochondrial function cause damage to cells of the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory systems, often compromising the life of those who suffer from them. The mitochondrial pathology known as succinate dehydrogenase (SDH) deficiency is an example of these devastating diseases. My laboratory uses the fruit fly, Drosophila melanogaster, as a model system. The fruit fly Drosophila is one of the most powerful model system used as a tool for genetics and drug screening. An essential prerequisite to realize this power is to construct a good model of the disease at the molecular level. Taking advantage of these characteristics, we have made an interesting observation: the drug rapamycin increases the activity of succinate dehydrogenase and increases mitochondria performance in flies with particular mitochondrial DNAs. This observation might prove to be an essential connection for a treatment of succinate dehydrogenase deficiency, and to identify novel nuclear-mitochondria effects modulating the disease. In this proposal we will test the hypothesis that rapamycin can protect form the pathology induced by SDH deficiency using D. melanogaster as a genetic model. This project will be performed by undergraduate students at Adelphi University. Here, at Adelphi, students already use D. melanogaster in biology classes to learn about genetics. We empathize in our classes the impact that research using this model system has in biology and medicine. With this project the students will be part of a research with potential impact in human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15GM113156-01
Application #
8812164
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Anderson, Vernon
Project Start
2015-04-01
Project End
2018-03-31
Budget Start
2015-04-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Adelphi University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
065972838
City
Garden City
State
NY
Country
United States
Zip Code
11530
Holmbeck, Marissa A; Donner, Julia R; Villa-Cuesta, Eugenia et al. (2015) A Drosophila model for mito-nuclear diseases generated by an incompatible interaction between tRNA and tRNA synthetase. Dis Model Mech 8:843-54
Villa-Cuesta, Eugenia; Rand, David M (2015) Preparation of Mitochondrial Enriched Fractions for Metabolic Analysis in Drosophila. J Vis Exp :