Figure 1. Axon-oligodendrocyte coupling in health and neurodegenerative disease. (A) In the healthy central nervous system, oligodendrocytes provide trophic support to axons by the transfer of energy-rich molecules (ie, lactate) from the oligodendroglial compartment to the axonal compartment. Lactate is released into the periaxonal space via MCT1 and is taken up by axons via MCT2, where it is used to fuel mitochondrial respiration. MBP acts as a zipper in the formation of compact myelin. In the neurodegenerative diseases AD (B), ALS (C), and MSA (D), pathological protein aggregates accumulate in the oligodendroglial cytoplasm and in the periaxonal space which could physically disrupt motor-driven transport and the free diffusion of metabolites (ie, lactate) from the oligodendroglial to the axonal compartment. In ALS, decreased expression of MCT1 would directly impair the ability of oligodendrocytes to provide metabolic support to axons. Demyelination is observed in all three diseases and it is associated with decreased expression of MBP in ALS and MSA. Impaired metabolic support together with mitochondrial dysfunction leads to decreased ATP supply and subsequent axonal dysfunction. Abbreviations: AD; Alzheimer disease, ALS; amyotrophic lateral sclerosis, FUS; fused in sarcoma, Glc; glucose, GLUT1; glucose transporter 1, Lac; lactate, MBP; myelin basic protein, MCT1; monocarboxylate transporter 1, MCT2; monocarboxylate transporter 2, MSA; multiple system atrophy, SOD1; superoxide dismutase 1, TDP43; transactive response DNA binding protein 43,TPPP/p25α; tubulin polymerization-promoting protein/p25α.