Modeling Neurodegenerative Diseases in the Fruit Fly

Abstract

Genetic studies in Drosophila have the potential to provide valuable insight into fundamental pathophysiologic mechanisms of human disease. As compared to early-onset neurological diseases such as those associated with inborn errors of metabolism, the pathogenesis of late-onset neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer’s, Parkinson’s, and Huntington’s diseases is proving to be complex. Given that a fundamental understanding of disease mechanisms is crucial to the rational design of therapeutic strategies, the myriad genetic techniques available in Drosophila for the study of biological phenomena might prove a useful addition to our current armamentarium of transgenic mice, in vitro and unicellular techniques, and biochemical studies. Classical genetic screens in Drosophila have uncovered numerous mutations giving rise to both ectopic developmental cell death and late-onset neuro-degeneration. Similarly, genetic study of fly homologs of human disease genes has provided important information about their function and pathological dysfunction. A more recent approach has utilized the targeted expression of mutant human disease genes in Drosophila to recapitulate certain aspects of human disease. Given that many aspects of cell death, signal transduction, cell cycle regulation, and pattern formation appear to be conserved in evolution from Drosophila to man, genetic screens for phenotypic modifiers of misexpressed mutant human genes may reveal similarly conserved modifier genes. Identification of such modifier genes might identify new therapeutic targets for otherwise incurable disorders.