Oligodendrocytes support axonal transport and maintenance via exosome secretion

• Published in: PLoS biology 2020-12, Vol.18 (12), p.e3000621-e3000621
• Main Authors: Frühbeis, Carsten, Kuo-Elsner, Wen Ping, Müller, Christina, Barth, Kerstin, Peris, Leticia, Tenzer, Stefan, Möbius, Wiebke, Werner, Hauke B, Nave, Klaus-Armin, Fröhlich, Dominik, Krämer-Albers, Eva-Maria
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Axonal transport; Axonal Transport - genetics; Axonal Transport - physiology; Axons; Axons - physiology; Biology and Life Sciences; Brain-derived neurotrophic factor; Centrifugation; Chromatography; Degeneration; Differential thermal analysis; Exosomes; Exosomes - metabolism; Exosomes - physiology; Extracellular Vesicles - metabolism; Extracellular Vesicles - physiology; Female; Glycoproteins; HEK293 Cells; Hippocampus; Homeostasis; Humans; Incubation; Liposomes; Maintenance; Male; Medicine and Health Sciences; Metabolism; Metabolites; Mice; Mice, Inbred C57BL; Myelin; Myelin proteolipid protein; Myelin Sheath - metabolism; Myelin-associated glycoprotein; Nervous system; Neurodegeneration; Neuroglia; Neurons; Neurons - metabolism; Neurons - physiology; Neurosecretion; Oligodendrocytes; Oligodendroglia; Oligodendroglia - metabolism; Oligodendroglia - physiology; Oxidative stress; Physical Sciences; Physiological aspects; Pretreatment; Properties; Proteins; Proteolipid protein; Protocol (computers); Research and Analysis Methods; Signal Transduction - physiology; Size exclusion chromatography; Transmission electron microscopy; Ultracentrifugation; Vesicles
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3000621

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 exosome secretion is impaired in 2 mouse mutants exhibiting secondary axonal degeneration due to oligodendrocyte-specific gene defects. Wild-type oligodendroglial exosomes support neurons by improving the metabolic state and promoting axonal transport in nutrient-deprived neurons. Mutant oligodendrocytes release fewer exosomes, which 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.