Glucose, ATP and the brain-keys to maintain neuronal health and graceful aging

Hui-Chen Lu

Director and Gill Chair for Linda and Jack Gill Center for Biomolecular Science
Professor in Dept. of Psychological & Brain Sciences
Indiana University

Résumé 

Neurons in the mammalian central nervous system often possess extensively arborized axonal processes that navigate over long distances to reach their targets. These complex axonal projections are a fundamental unit of brain circuits, where they direct information flow underlying behaviors and cognitive function. Active and well supported axonal transport of specific cargos between cell bodies and axonal terminals is critical in supporting neuronal function and survival. Axonal transport is an ATP demanding process. ATP in neurons is synthesized by glycolysis and mitochondrial respiration, both driven by proper NAD+/NADH redox potentials.  NMNAT2 is the major neuronal NAD+ synthesizing enzyme and is a key axonal maintenance factor.  We find that NMNAT2 co-migrates with fast vesicular cargos and is required for fast axonal transport in the distal axons of cortical neurons. Using SoNar sensor imaging to detect axonal NAD+ and NADH, we show that NMNAT2 is critical in maintaining NAD+/NADH potentials in distal axons. With Syn-ATP sensor imaging to detect synaptic vesicle ATP levels (sv-ATP), we demonstrate that glycolysis is the major provider of sv-ATP and NMNAT2 deletion significantly reduces sv-ATP levels. NAD+ supplementation of NMNAT2 KO neurons restores sv-ATP levels and fast axonal transports in a glycolysis-dependent manner. Together, our data show that NMNAT2 maintains the local NAD+/NADH redox potential and sustains “on-board” glycolysis to meet the bioenergetic demands of fast vesicular transport in distal axons.

Invitée par Olivier Manzoni

Lundi 13 juin à 11h – salle de conférence de l’Inmed