Abstract
Neurons extend long axons that require maintenance and are susceptible to degeneration. Long-term integrity of axons depends on intrinsic mechanisms including axonal transport and extrinsic support from adjacent glial cells. The mechanisms of support provided by myelinating oligodendrocytes to underlying axons are only partly understood. Oligodendrocytes release extracellular vesicles (EVs) with properties of exosomes, which upon delivery to neurons improve neuronal viability in vitro. Here, we show that oligodendroglial exosomes support neurons by promoting fast axonal transport, most strikingly under conditions of oxidative stress and nutrient deprivation. Interestingly, oligodendroglial exosome secretion is impaired in two mouse mutants exhibiting secondary axonal degeneration due to oligodendrocyte-specific gene defects. Mutant oligodendrocytes release less exosomes that share a common signature of underrepresented proteins. Notably, mutant exosomes lack the ability to support nutrient deprived neurons and to promote axonal transport. Together, these findings indicate that glia to neuron exosome transfer promotes neuronal long-term maintenance by facilitating axonal transport, providing a novel mechanistic link between myelin diseases and secondary loss of axonal integrity.
