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 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.
Highlights
Extracellular vesicles (EVs) are a heterogeneous group of secreted vesicles that appear to be engaged in a wide range of neural cell communication processes and have been implicated in neural development, maintenance, neurodegeneration, and regeneration [1,2,3]
Oligodendroglial small extracellular vesicle (sEV) with exosomal properties promote fast axonal transport To explore the functional role of oligodendroglial exosomes in oligodendrocyte–neuron interaction and glial support, we examined their impact on fast axonal transport
Applying the same sEV treatment protocol to brain-derived neurotrophic factor (BDNF)-mCherry-expressing hippocampal neurons (15 h of pretreatment followed by 1 h of oxidative stress and imaging), we found that oligodendroglial sEVs significantly increased anterograde vesicle movement and decreased the pool of static vesicles, while retrograde movement and velocities were unaffected (S2 Fig)
Summary
Extracellular vesicles (EVs) are a heterogeneous group of secreted vesicles that appear to be engaged in a wide range of neural cell communication processes and have been implicated in neural development, maintenance, neurodegeneration, and regeneration [1,2,3]. According to their site of biogenesis, EVs can be subclassified as exosomes, which are released from the lumen of secretory multivesicular bodies (MVBs), and microvesicles, which are shed from the plasma membrane [4,5].
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