Manzo, E., Lorenzini, I., Barrameda, D., O'Conner, A.G., Barrows, J.M., Starr, A., Kovalik, T., Rabichow, B.E., Lehmkuhl, E.M., Shreiner, D.D., Joardar, A., Liévens, J.C., Bowser, R., Sattler, R., Zarnescu, D.C. (2019). Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS.  eLife 8(): e45114.

FBrf0242626

Research paper

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.

PMC6557627 (PMC) (EuropePMC)