Amyotrophic Lateral Sclerosis (ALS), is a fatal neurodegenerative disorder, with TDP-43 inclusions as a major pathological hallmark. Using a Drosophila model of TDP-43 proteinopathy we found significant alterations in glucose metabolism including increased pyruvate, suggesting that modulating glycolysis may be neuroprotective. Indeed, a high sugar diet improves locomotor and lifespan defects caused by TDP-43 proteinopathy in motor neurons or glia, but not muscle, suggesting that metabolic dysregulation occurs in the nervous system. Overexpressing human glucose transporter GLUT-3 in motor neurons mitigates TDP-43 dependent defects in synaptic vesicle recycling and improves locomotion. Furthermore, PFK mRNA, a key indicator of glycolysis, is upregulated in flies and patient derived iPSC motor neurons with TDP-43 pathology. Surprisingly, PFK overexpression rescues TDP-43 induced locomotor deficits. These findings from multiple ALS models show that mechanistically, glycolysis is upregulated in degenerating motor neurons as a compensatory mechanism and suggest that increased glucose availability is protective.
Digital Object Identifier (DOI)
Manzo, Ernesto; Lorenzini, Ileana; Barrameda, Dianne; O'Conner, Abigail G.; Barrows, Jordan M.; Starr, Alexander; Kovalik, Tina; Rabichow, Benjamin E.; Lehmkuhl, Erik M.; Shreiner, Dakotah D.; Joardar, Archi; LiÃ©vens, Jean Charles; Bowser, Robert; Sattler, Rita; and Zarnescu, Daniela C., "Glycolysis Upregulation Is Neuroprotective As A Compensatory Mechanism In Als" (2019). Translational Neuroscience. 17.