Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS

• DOI: 10.7554/elife.45114
• Publication Date: 2019-06-10T15:00:22Z
• Authors: Ernesto Manzo; Ileana Lorenzini; Dianne Barrameda; Abigail G O'Conner; Jordan M Barrows; Alexander Starr; Tina Kovalik; Benjamin E Rabichow; Erik M Lehmkuhl; Dakotah D Shreiner; Archi Joardar; Jean-Charles Liévens; Robert Bowser; Rita Sattler; Daniela C Zarnescu
• Keywords: Carbohydrate Metabolism

Amyotrophic Lateral Sclerosis (ALS), is a fatal neurodegenerative disorder, with TDP-43 inclusions as major pathological hallmark. Using Drosophila model of proteinopathy we found significant alterations in glucose metabolism including increased pyruvate, suggesting that modulating glycolysis may be neuroprotective. Indeed, high sugar diet improves locomotor and lifespan defects caused by motor neurons or glia, but not muscle, metabolic dysregulation occurs the nervous system. Overexpressing human transporter GLUT-3 mitigates dependent synaptic vesicle recycling locomotion. Furthermore, PFK mRNA, key indicator glycolysis, upregulated flies patient derived iPSC pathology. Surprisingly, overexpression rescues induced deficits. These findings from multiple ALS models show mechanistically, degenerating compensatory mechanism suggest availability protective.