While most forms of ALS occur in adulthood, mutations in the gene termed Serine Palmitoyltransferase Long Chain Base Subunit 1 (SPTLC1) arise in children. In these children, the disease course is longer but nevertheless results in loss of control of muscles. It is not known why ALS manifests at younger ages nor is understood exactly how motor neurons succumb to disease in these patients. SPTCL1 is an enzyme that is involved in the formation of lipids which neurons use to make membranes. Studies using cell models suggest that in these patients, certain lipids, that are normally produced in small quantities, are over produced, and become toxic to motor neurons. In our grant we propose to generate zebrafish models expressing ALS-causing mutations of human SPTLC1. We will than use these models to further our understanding of how motor neurons degenerate in this form of ALS. We will then evaluate two potential avenues that could be translated clinically. The first approach will be to test a gene therapy that removes the mutant transcript in one of our fish models and the second approach will be to test pharmacological inhibitors of the pathway that over produces the lipids that affect motor neuron survival. Our project will further our understanding of juvenile forms of ALS and hopefully provide data pertaining to future treatments.
