Oligodendrocytes support axonal transport and maintenance via exosome secretion

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.Here, we studied the effect of oligodendroglial sEVs on axonal maintenance and examined their impact on fast axonal transport by live-cell imaging of vesicular cargo travelling along axons. We show that adding sEVs to neurons promotes axonal transport most prominently under conditions of cell stress. Intriguingly, we found that the release of sEVs from PLP-and CNP-deficient oligodendrocytes is impaired and that mutant sEVs, which share a common altered proteome signature, are dysfunctional. We conclude that sEVs of exosomal nature delivered from oligodendrocytes to neurons contribute to axonal homeostasis and long-term maintenance by facilitating axonal transport. Secondary axonal degeneration, as observed in PLP-and CNP-deficient mice, is coupled to glial exosome function providing a so far missing link between glial dysfunction, axonal transport and axonal degeneration as seen in various neurological diseases.

Simultaneous Inhibition of Glycolysis and Oxidative Phosphorylation Triggers a Multi-Fold Increase in Secretion of Exosomes: Possible Role of 2′,3′-cAMP

“…They also reported that oligodendrocyte-derived exosomes are taken up by neurons and facilitate axonal transport. Notably, exosomes from CNPase knockout cells lack the ability to support nutrient deprived neurons and to promote axonal transport 32 .…”

Neuron-Oligodendrocyte Interactions in the Structure and Integrity of Axons

“…Nevertheless, with conditional ablation of the Fth1 gene in adulthood the neuronal loss occurred in the absence of detectable disruption to myelin ( Mukherjee et al, 2020 ), arguing against this interpretation. Reduced EV release is seen in oligodendrocytes derived from Plp1 and Cnp1 null mice, both of which display progressive axonal degeneration ( Frühbeis et al, 2020 ). Together, these results identify the secretion of EVs from oligodendrocytes as a potentially important mechanism for axonal support by oligodendrocytes.…”

Extracellular Vesicles in neural cell interaction and CNS homeostasis

“…1E). Intriguingly, mice with secondary axonal degeneration due to the lack of the glial proteins PLP and CNP exhibit impaired oligodendroglial EV release and have lost the ability to promote axonal transport (53). EV transfer from oligodendrocytes to neurons may thus provide a means of support, essential for long-term neuronal survival and axonal maintenance.…”

“…Conditional knockout of Rab35 (CNP Cre/+ /Rab35 fl/fl mice) has been recently used to interfere with EV-release from oligodendrocytes demonstrating that cortical neurons degenerate due to oxidative damage when they do not receive oligodendroglial EVs (54). Furthermore, null mutants of oligodendroglial PLP or CNP (representing EV cargo) are characterized by impaired EV-release and suffer from axonal degeneration providing genetic evidence that oligodendroglial EVs provide essential support to axons (53). Additional studies looking at the functional impact of impeded EV-release and transfer between brain cells are required to uncover the likely broad range of EV functions in the brain.…”