Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS

• Published in: eLife 2019-06, Vol.8
• Main Authors: 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, Liévens, Jean-Charles, Bowser, Robert, Sattler, Rita, Zarnescu, Daniela C
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Defects; Disease Models, Animal; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Drosophila; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Economic indicators; Enzymes; Experiments; Fractions; Glucose; Glucose - metabolism; Glucose transporter; Glucose Transporter Type 3 - genetics; Glucose Transporter Type 3 - metabolism; Glycolysis; Health aspects; human; Humans; Insects; iPSC; Life Sciences; Life span; Locomotion; Messenger RNA; Metabolism; Metabolites; Motor neurons; Motor Neurons - metabolism; mRNA; Nervous system; Nervous system diseases; Neurobiology; Neurodegenerative diseases; Neuronal-glial interactions; Neurons; Neurons and Cognition; Neuroprotection; Neuroprotection - genetics; Neuroscience; Neurosciences; Patients; Physiological aspects; Pyruvic acid; Pyruvic Acid - metabolism; RNA; Sugar; Transcriptional Activation; Up-Regulation
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.45114

Amyotrophic Lateral Sclerosis (ALS), is a fatal neurodegenerative disorder, with TDP-43 inclusions as a major pathological hallmark. Using a 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, mRNA, a key indicator of glycolysis, is upregulated in flies and patient derived iPSC motor neurons with TDP-43 pathology. Surprisingly, 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.