937C Poster - 15. Models of human disease
Saturday April 09, 1:30 PM - 3:30 PM

Authors:
Nicholas Mortimore ¹; Suvithanandhini Loganathan ¹; Hannah Ball ¹; Maria Macias ¹; MyDuyen Tran ¹; Gabrielle Peterson ¹; Gabriel Birchak ^1,3; Ernesto Manzo ^1,4; Daniela Zarnescu ^1,2

Affiliations:
1) Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ; 2) Department of Neuroscience, University of Arizona, Tucson, AZ; 3) University of Pennsylvania, Philadelphia, PA; 4) Vollum Institute, Oregon Health and Science University, Portland, OR

Keywords:
a. neural degeneration; b. metabolism

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that affects upper and lower motor neurons primarily in individuals aged forty years or greater. ALS causes loss of motor control, paralysis, and eventually respiratory failure and death within 2-5 years of diagnosis; there is no known cure for this disease. TAR DNA-binding protein (TDP-43) is a pathological marker of ALS and aggregation of TDP-43 is observed in 97% of ALS cases. Our lab has generated a Drosophila model of ALS based on overexpression of human TDP-43 in a motor-neuron specific manner which recapitulates key disease phenotypes including cytoplasmic accumulation of TDP-43, neuromuscular junction (NMJ) abnormalities, decreased lifespan, and locomotor defects. Glycolysis upregulation by an increase in Phosphofructokinase-1 (PFK1; PFK in Drosophila) has been shown to have a neuroprotective effect in Drosophila models of ALS based on TDP-43 proteinopathy. Here we aim to decipher the mechanisms underlying the restorative effect of PFK overexpression (OE) in ALS. One possible mechanism is that PFK assembles in complexes that support energy demands locally, at synapses. Supporting this scenario are our observations that PFK forms puncta within Drosophila NMJs in the context of mutant TDP-43 OE. This is consistent with recent evidence from other groups showing that PFK can form clusters at the synapses of C. elegans where it associates with other glycolytic enzymes to form Glycolytic bodies (G-bodies) and supports synaptic vesicle cycling under stress. Our preliminary data support this hypothesis as evidenced by FM1-43 dye uptake experiments showing that PFK OE rescues TDP-43 induced synaptic vesicle cycling deficits. Another possible mechanism is that pyruvate, the end product of glycolysis, which was found to be increased in multiple ALS models may act as a scavenger of reactive oxygen species as shown in cancer cells. We are currently interrogating the composition of G-bodies with mass spectrometry analyses of PFK complexes to further test the hypothesis that G-body composition is altered in the context of TDP-43 proteinopathy. These findings may inform novel therapeutic strategies based on improved cellular energetics for ALS and related neurodegenerative disorders.