Metabolic Alterations and Targeted Therapies in a Drosophila Model of ALS
AdvisorZarnescu, Daniela C.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction, presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractAmyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. Despite one hundred and fifty years since the first characterization of the disease, an effective treatment for patients has remained elusive. ALS patients often present with systemic metabolic defects that correlate with disease progression. Exactly how metabolic alterations contribute to disease pathogenesis is poorly understood. Our laboratory has developed a Drosophila model of ALS based on the genetic overexpression of TAR DNA binding protein 43 (TDP-43), a protein that is found in pathological aggregates in over 97% of all ALS patients. Using this model, we find metabolic alterations in long chain fatty acids and glycolysis end-products - suggesting altered mitochondrial function and altered glucose metabolism. Dietary supplementation with either medium chained fatty acids, ketone precursors, or glucose improves the locomotor function of TDP-43 expressing flies. Indeed, increased glucose availability through genetic expression of human glucose transporter 3 in motor neurons improves TDP-43 induced locomotor defects, improves synaptic vesicle function, and increases the number of boutons at the neuromuscular junction. Moreover, Pfk mRNA, an indicator of glycolytic flux, is upregulated in flies, patient derived motor neurons differentiated from induced pluripotent stem cells and ALS spinal cords. Interestingly, Pfk overexpression rescues TDP-43 induced locomotor defects – suggesting that increasing the rate of glycolysis in motor neurons is neuroprotective. Together, these findings show that there are clear metabolic alterations in the central nervous system of a Drosophila model of ALS that can be mitigated by either increasing the availability of medium-chained fatty acids, or increasing the rate of glycolysis.
Degree ProgramGraduate College
Molecular & Cellular Biology