PgmNr D1359: Altered metabolism in a TDP-43 model of ALS in Drosophila.

Authors:
Abigail O'Conner; Ernesto Manzo; Sylvia Zarnescu; Mary-Beth Roberts; Daniela Zarnescu


Institutes
University of Arizona, Tucson, AZ.


Keyword: neural degeneration

Abstract:

ALS, or amyotrophic lateral sclerosis, is a fatal progressive neurodegenerative disease for which there is currently no cure. Several genes have been linked to ALS, including TDP-43, which encodes an RNA binding protein and has been associated with the vast majority of ALS cases. While only 2-3% of ALS cases harbor mutations in TDP-43, more than 95% of patients exhibit TDP-43 positive cytoplasmic inclusions. A Drosophila model of ALS using both wild-type and mutant TDP-43 expression has been shown to recapitulate several pathogenic hallmarks of the disease, including motor dysfunction and decreased survival.

Because metabolic changes have been seen in ALS patients, we have investigated whether similar defects are also present in our fly model. Indeed, metabolomics studies show that, as in ALS patients, flies expressing TDP-43 in motor neurons exhibit a significant increase in pyruvate, the end product of glycolysis, and alterations in the TCA cycle. Using a larval locomotion assay that quantifies differences in locomotor function, we have tested the effects of dietary changes on larvae expressing TDP-43 in motor neurons or glia. Increased dietary glucose appears to alleviate motor dysfunction in wild-type and mutant larvae (both in motor neuronal and glial expression), while also increasing survival time in adult flies. Consistent with these findings, expression of the glucose transporter GLUT4 in diseased larvae shows a similar improvement in motor function. Additionally, the introduction of different fats into the diet of larvae expressing TDP-43 in motor neurons appears to improve motor function at specific dosages. Taken together, these data suggest that the TDP-43 based fly model of ALS experiences specific alterations in metabolism that parallel the changes seen in patients and offer novel strategies for therapeutic and dietary intervention for ALS.