Investigator: Geoff Stillwell, Rhode Island College

Mentor: Robert Reenan, Brown University

Scientific Theme: Neuroscience & Molecular Toxicology

Abstract: Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease that causes progressive motor neuron degeneration and leads to muscle weakness and death in afflicted individuals. The average survival time is 3 years after diagnosis and Riluzole, the only approved therapeutic, shows minimal increases in survival time. Familial forms of the disease produce similar or identical pathologies and have been used extensively to model the human disease state. Mutations in the superoxide dismutase 1 (SOD1) were first described 20 years ago and more than 150 mutations in this gene have been documented in patients to date. In well-characterized mouse SOD models, disease pathogenesis appear to be a consequence of protein aggregation; however, it is still unclear which cellular and molecular changes are considered critical and relevant to ALS pathogenesis due to significant phenotypic variability in the animal models combined with the non-physiological expression levels of mutant SOD protein.

To address the issue of variability within the genetic models and to address questions relating to pathogenic events, we will develop and characterize novel ALS models using homologous recombination to insert disease-associated mutations into the endogenous SOD gene of the genetically tractable model organism Drosophila melanogaster. The overall objective of this program is to create and characterize a series of mutant SOD alleles within a single isogenic background to allow for direct comparisons between alleles and characterize the resulting biological events leading to toxicity. As a first specific aim, we will first use homologous recombination to ‘knock-in’ two SOD mutations that exhibit seemly differential toxicity and characterize the effects in flies. As a second aim, will conduct forward genetic screens to identify enhancers of toxicity and use methods developed previously to adapt this model for well-based high-throughput screening in vivo screening to identify chemical suppressors of toxicity. This research will enhance collaborations between investigators at Brown University and Rhode Island College.

Human Health Relevance: This proposal aims to investigate the events leading to motor neuron death in Amyotrophic Lateral Sclerosis in a translational model that could also be used to find new drug targets and therapeutic compounds. This project represents collaborative efforts between scientists at Rhode Island College and Brown University and will provide undergraduates at Rhode Island College the opportunity to engage in translational research.