Genetic Mechanisms of Motor Neuron Degeneration

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DESCRIPTION (provided by applicant): Genetic Mechanisms of Motor Neuron Degeneration Amyotrophic lateral sclerosis (ALS) is a fatal late-onset disease caused by the progressive degeneration of motor neurons. Although there has been considerable progress in the identification of genes linked to inherited cases of ALS, the etiology of this disease remains largely unknown. The lack of effective therapeutic treatments for patients diagnosed with ALS further underscores the importance of research directed at understanding the causes of this devastating disease. However, the identification of causative genes of ALS has been severely hindered by the lack of a simple laboratory model of motor neuron degeneration. The fruit fly Drosophila has played an instrumental role in our understanding of the pathogenesis of many human neurodegenerative diseases. The majority of Drosophila genes are highly conserved and, as a consequence, it is estimated that there is a homologous Drosophila gene for over 75% of human disease-causing genes. Furthermore, the relative simplicity of its neuromuscular system makes Drosophila an ideal model to study the genetic mechanisms underlying motor neuron degeneration. By creating genetic mosaics in Drosophila, our research allows us to visualize, with exquisite resolution, the phenotypic effects of deleterious mutations within a single motor neuron. This project will identify novel genes linked to motor neuron degeneration and determine the pathological basis of motor dysfunction in identified mutants using motor behavior assays. It is expected that this project will establish a novel Drosophila model of motor neuron degeneration that will significantly expand our current understanding of the etiology and pathogenesis of ALS and will further provide novel gene targets for future therapeutic research. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with no known cure. The proposed project will identify new genes linked to the progressive degeneration of motor neurons, significantly expanding our current understanding of the etiology and pathogenesis of ALS.