Schwann cell autophagy, myelinophagy, initiates myelin clearance from injured nerves

Gomez-Sanchez, Jose A.; Carty, Lucy; Iruarrizaga‐Lejarreta, Marta; Palomo-Irigoyen, Marta; Varela‐Rey, Marta; Griffith, Megan; Hantke, Janina; Macías-Cámara, Nuria; Azkargorta, Mikel; Aurrekoetxea, Igor; Juan, Virginia Gutiérrez de; Jefferies, Harold B.J.; Aspichueta, Patricia; Elortza, Félix; Aransay, Ana M.; Martínez‐Chantar, María Luz; Baas, Frank; Mato, José M.; Mirsky, Rhona; Woodhoo, Ashwin; Jessen, Kristján R.

doi:10.1083/jcb.201503019

Cited by 365 publications

(421 citation statements)

References 47 publications

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“…Although not significant, the proportion of autophagy structures had also decreased in unmyelinated axons while it was increased in Schwann cells at follow-up. Indeed, it has recently been reported that Schwann cells use autophagy as a degradation process (Gomez-Sanchez et al, 2015;Jang et al, 2016). Obviously, the autophagy pathway is affected in both axons and Schwann cells in longterm diabetes.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal study of neuropathy, microangiopathy, and autophagy in sural nerve: Implications for diabetic neuropathy

et al. 2017

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Objectives: The progression and pathophysiology of neuropathy in impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) is poorly understood, especially in relation to autophagy. This study was designed to assess whether the presence of autophagyrelated structures was associated with sural nerve fiber pathology, and to investigate if endoneurial capillary pathology could predict the development of T2DM and neuropathy. Patients and Methods:Sural nerve physiology and ultrastructural morphology were studied at baseline and 11 years later in subjects with normal glucose tolerance (NGT), IGT, and T2DM.Results: Subjects with T2DM had significantly lower sural nerve amplitude compared to subjects with NGT and IGT at baseline. Myelinated and unmyelinated fiber, endoneurial capillary morphology, and the presence and distribution of autophagy structures were comparable between groups at baseline, except for a smaller myelinated axon diameter in subjects with T2DM and IGT compared to NGT. The baseline values of the subjects with NGT and IGT who converted to T2DM 11 years later demonstrated healthy smaller endoneurial capillary and higher g-ratio versus subjects who remained NGT. At follow-up, T2DM showed a reduction in nerve conduction, amplitude, myelinated fiber density, unmyelinated axon diameter, and autophagy structures in myelinated axons. Endothelial cell area and total diffusion barrier was increased versus baseline. Conclusions:We conclude that small healthy endoneurial capillary may presage the development of T2DM and neuropathy. Autophagy occurs in human sural nerves and can be affected by T2DM. Further studies are warranted to understand the role of autophagy in diabetic neuropathy. K E Y W O R D Sautophagy, diabetes, endoneurial capillary, impaired glucose tolerance, morphometry, peripheral neuropathy

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Section: Discussionmentioning

confidence: 99%

Longitudinal study of neuropathy, microangiopathy, and autophagy in sural nerve: Implications for diabetic neuropathy

et al. 2017

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“…Schwann cells in the distal nerve stump lose their axonal attachment, proliferate and resorb myelin. Autophagy of myelin by Schwann cells provides the rate-limiting mechanism for myelin clearance and depends on JNK/c-Jun (Gomez-Sanchez et al, 2015). The initial signal for the Schwann cell response appears to be provided by axons, as Wallerian degeneration slow (Wlds) mouse mutants whose axon destruction is delayed also show gross delays in myelin removal and nerve regeneration.…”

Section: Nrg1 and Remyelination After Injurymentioning

confidence: 99%

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

Birchmeier

Bennett

2016

Current Topics in Developmental Biology

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Myelin is essential for rapid and accurate conduction of electrical impulses by axons in the central and peripheral nervous system. Myelin is formed in the early postnatal period, and developmental myelination in the peripheral nervous system (PNS) depends on axonal signals provided by Nrg1/ErbB receptors. In addition, Nrg1 is required for effective nerve repair and remyelination in adulthood. We discuss here similarities and differences in Nrg1/ErbB functions in developmental myelination and remyelination after nerve injury.

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“…To test whether autophagy is necessary for Schwann cell degradation of myelin after nerve crush injury, as has recently been shown after nerve transection, we generated mice in which Schwann cells are unable to perform autophagy due to deletion of essential autophagy protein atg7 (floxed Atg7 × P0 Cre) (20)(21)(22). These mice did not display any obvious behavioral abnormalities before their use for experiments at 8 to 12 wk of age.…”

Section: Assessment Of the Role Of Autophagy In Myelin Debris Clearancementioning

confidence: 99%

Schwann cells use TAM receptor-mediated phagocytosis in addition to autophagy to clear myelin in a mouse model of nerve injury

Lutz

Chung

Sloan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

178

160

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Ineffective myelin debris clearance is a major factor contributing to the poor regenerative ability of the central nervous system. In stark contrast, rapid clearance of myelin debris from the injured peripheral nervous system (PNS) is one of the keys to this system's remarkable regenerative capacity, but the molecular mechanisms driving PNS myelin clearance are incompletely understood. We set out to discover new pathways of PNS myelin clearance to identify novel strategies for activating myelin clearance in the injured central nervous system, where myelin debris is not cleared efficiently. Here we show that Schwann cells, the myelinating glia of the PNS, collaborate with hematogenous macrophages to clear myelin debris using TAM (Tyro3, Axl, Mer) receptor-mediated phagocytosis as well as autophagy. In a mouse model of PNS nerve crush injury, Schwann cells up-regulate TAM phagocytic receptors Axl and Mertk following PNS injury, and Schwann cells lacking both of these phagocytic receptors exhibit significantly impaired myelin phagocytosis both in vitro and in vivo. Autophagy-deficient Schwann cells also display reductions in myelin clearance after mouse nerve crush injury, as has been recently shown following nerve transection. These findings add a mechanism, Axl/Mertk-mediated myelin clearance, to the repertoire of cellular machinery used to clear myelin in the injured PNS. Given recent evidence that astrocytes express Axl and Mertk and have previously unrecognized phagocytic potential, this pathway may be a promising avenue for activating myelin clearance after CNS injury.

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Schwann cell autophagy, myelinophagy, initiates myelin clearance from injured nerves

Abstract: Schwann cells degrade myelin after injury by a novel form of selective autophagy, myelinophagy, which is positively regulated by the JNK/c-Jun pathway and is defective in the injured central nervous system.

Cited by 365 publications

References 47 publications

Longitudinal study of neuropathy, microangiopathy, and autophagy in sural nerve: Implications for diabetic neuropathy

Longitudinal study of neuropathy, microangiopathy, and autophagy in sural nerve: Implications for diabetic neuropathy

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

Schwann cells use TAM receptor-mediated phagocytosis in addition to autophagy to clear myelin in a mouse model of nerve injury

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