Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS

Ernesto Manzo , Ileana Lorenzini , Dianne Barrameda , Abigail O'Conner , Jordan Barrows , Alexander Starr , Tina Kovalik , Benjamin Rabichow , Erik Lehmkuhl , Dakotah Shreiner , Archi Joardar , Jean-Charles Liévens (1) , Robert Bowser , Rita Sattler , Daniela Zarnescu

1 MMDN - Mécanismes moléculaires dans les démences neurodégénératives

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.

Mots clés: D. melanogaster; drosophila; human; iPSC; neuroscience

Domaines: Neurobiologie

Ernesto Manzo, Ileana Lorenzini, Dianne Barrameda, Abigail O'Conner, Jordan Barrows, et al.. Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS. eLife, 2019, 8, ⟨10.7554/eLife.45114⟩. ⟨hal-03005486⟩