Neuronal loss of the pentose phosphate pathway in the living nervous system is causally linked to [NADPH] reduction and elevated oxidative stress.

Neurons are highly specialized cells that require large amounts of energy to function. Glial cells support neurons in many ways, including metabolically. In Drosophila, neuronal glycolysis has been found to be dispensable, as long as glial glycolysis is intact, a finding supporting a conservation of the astrocyte-neuron-lactate shuttle (i.e. ANLS)-hypothesis. Neurons use glia-derived lactate to fuel their highly oxidative metabolism. Nevertheless, they readily take up glucose. It has been hypothesized that neuronal glucose might be pre-dominantly metabolized through the pentose phosphate pathway (PPP) rather than glycolysis to produce reduction equivalents in the form of NADPH to cope with the oxidative stress caused by a highly oxidative metabolism and prevent oxidative damage. We show that knockdown of components of the PPP in all neurons in Drosophila induces mild neurodegeneration, which can be rescued by antioxidant feeding. To directly link a putative loss of neuronal NADPH to elevated reactive oxygen species (ROS), we generated fly lines expressing biosensors for NADPH and H