Fig. 1

A simplified summary of CNS glucose metabolism, and commonly observed defects in amyotrophic lateral sclerosis (ALS). Glucose enters into neurons via glucose transporter (GLUT3) and via GLUT1 into astrocytes. In this figure, the astrocyte foot process is shown wrapping around the capillary. Then, glucose is phosphorylated by hexokinase (HK) to glucose 6-phosphate (G6P). G6P can be converted by glucose 6-phosphate dehydrogenase (G6PDH) to 6-phospho gluconolactone to enter the pentose phosphate pathway (PPP), where it is converted by a series of enzymatic reactions to subsequent PPP intermediates, such as R5P (ribose 5-phosphate) which later can enter the glycolytic pathway via glyceraldehyde 3-phosphate (G3P) or provide nucleotide backbones. G6P may also be converted to glucose 1-phosphate which is utilized for glycogen synthesis. If G6P continues through glycolysis, it is converted into F6P (fructose 6 phosphate) and later to fructose 1,6-bisphosphate (F16BP) by phosphofructokinase (PFK). F16BP is further metabolised to glyceraldehyde 3-phosphate (G3P), phosphoenol pyruvate (PEP) and pyruvate, by a series of enzymatic processes including pyruvate kinase (PK) which converts PEP into pyruvate. Pyruvate can be reduced to lactate by lactate dehydrogenase or enters mitochondria via mitochondrial pyruvate carrier (MPC) and gets converted into acetyl CoA by pyruvate dehydrogenase (PDH). Acetyl-CoA condenses with oxaloacetate to citrate and thereby enters the tricarboxylic acid (TCA) cycle. The TCA cycle generates different TCA cycle intermediates, including α-ketoglutarate (α-KG) from which glutamate can be synthesized. During neurotransmission, glutamate is released from the presynaptic vesicles into the synapse where it is taken up by glutamate transporters in astrocytes and then converted into glutamine (Gln) by glutamine synthetase (GS). Gln can also be transferred into neurons and gets converted into Glu by phosphate activated glutaminase (PAG), completing the Glu-Gln shuttle. In GABAergic neurons, Glu is converted into GABA by glutamate decarboxylase (GAD) enzyme. The TCA cycle also generates reducing equivalents such as nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide, which transfer electrons to oxygen via the enzyme complexes of the electron transport chain, ultimately resulting in the generation of ATP. In ALS, numerous metabolic defects (shown in red) at various steps in the glucose metabolism pathway that alter glucose metabolism and overall ATP generation have been described. This include impairments in glucose transport (changes in glucose transporter expression or HK activities), glycolysis (reduced activities of pyruvate kinase and phosphoglycerate kinase, reduced levels of lactate and reduced activities of PK), and PPP (reduced activities of G6PDH and reduced levels of R5P), increased glycogen accumulation, reduced entry of pyruvate into the TCA cycle (increased protein levels of PDH kinase 1, which downregulates PDH activity; reduced activities of oxoglutarate dehydrogenase (OGDH)), mitochondrial dysfunction, reduced mitochondrial ATP production, increased reactive oxygen species (ROS) production, as well as abnormal neuronal-glial interactions (reduced transfer of glutamate to glutamine, and glutamate excitotoxicity)