MECHANISMS UNDERLYING THE PROTECTIVE EFFECT OF GLYCOLYSIS

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that disrupts muscle function and has no cure. TAR DNA Binding Protein (TDP-43) is an RNA binding protein that has been found in cytoplasmic aggregates in 97% of ALS cases regardless of etiology. Drosophila is a well-established genetic model for human disease that we used to develop a model for ALS based on TDP-43. Flies expressing either wild-type or mutant human TDP-43 (TDP-43WT and TDP-43G298S) recapitulate several symptoms of ALS, including motor neuron dysfunction and reduced survival. Recently, we found that glycolysis is upregulated in this model as a compensatory mechanism that improves locomotor function and increases lifespan. To elucidate the mechanism by which glycolysis is neuroprotective in ALS we are investigating the role of phosphofructokinase (PFK), the rate limiting enzyme of glycolysis in the context of TDP-43 proteinopathy. Preliminary results using a GFP tagged PFK CRISPR line show that PFK exhibits a different localization in the context of TDP-43 compared to control motor neurons. In addition, over-expression of PFK rescues various TDP-43 dependent phenotypes including synaptic vesicle endocytosis defects