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

Gomez-Sanchez JA, Carty L, Iruarrizaga-Lejarreta M, Palomo-Irigoyen M, Varela-Rey M, Griffith M, Hantke J, Macias-Camara N, Azkargorta M, Aurrekoetxea I, De Juan VG, Jefferies HB, Aspichueta P, Elortza F, Aransay AM, Martínez-Chantar ML, Baas F, Mato JM, Mirsky R, Woodhoo A, Jessen KR - J. Cell Biol. (2015)

Bottom Line: Myelinophagy was positively regulated by the Schwann cell JNK/c-Jun pathway, a central regulator of the Schwann cell reprogramming induced by nerve injury.We also present evidence that myelinophagy is defective in the injured central nervous system.These results reveal an important role for inductive autophagy during Wallerian degeneration, and point to potential mechanistic targets for accelerating myelin clearance and improving demyelinating disease.

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Affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, England, UK.

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Regulation of myelinophagy. (A and B) Graph showing reduced LC3 II accumulation in nerve segments (A) maintained in vitro for 5 d and treated with JNK inhibitor in the presence and absence of NH4Cl (3 h treatment) and in nerve segments (B) maintained in vitro for 5 d from cJun cKO mice compared with WT mice, in the presence and absence of NH4Cl (3 h treatment). Graphs show reduced net LC3 II flux. Data are presented as mean ± SEM (error bars) from three independent experiments. **, P < 0.01 (treated cells relative to untreated cells; cJun cKO relative to WT). (C) Western blots showing elevated LC3 II levels in uninjured C3 nerves compared with WT nerves. The graph shows densitometric quantification of blots. n = 3 mice for each genotype. Data are presented as mean ± SEM (error bars). *, P < 0.05 (C3 mice relative to WT). (D) Western blots showing that LC3 II levels in optic nerves are substantially lower than in sciatic nerve 3 and 5 d after cut. The graph shows densitometric quantification of blots. Data are presented as mean ± SEM (error bars) from three independent experiments. *, P < 0.05 (sciatic nerves relative to optic nerves); **, P < 0.01 (cut sciatic nerves relative to uncut nerves); n.s., not significant (cut optic nerves relative to uncut nerves).
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fig7: Regulation of myelinophagy. (A and B) Graph showing reduced LC3 II accumulation in nerve segments (A) maintained in vitro for 5 d and treated with JNK inhibitor in the presence and absence of NH4Cl (3 h treatment) and in nerve segments (B) maintained in vitro for 5 d from cJun cKO mice compared with WT mice, in the presence and absence of NH4Cl (3 h treatment). Graphs show reduced net LC3 II flux. Data are presented as mean ± SEM (error bars) from three independent experiments. **, P < 0.01 (treated cells relative to untreated cells; cJun cKO relative to WT). (C) Western blots showing elevated LC3 II levels in uninjured C3 nerves compared with WT nerves. The graph shows densitometric quantification of blots. n = 3 mice for each genotype. Data are presented as mean ± SEM (error bars). *, P < 0.05 (C3 mice relative to WT). (D) Western blots showing that LC3 II levels in optic nerves are substantially lower than in sciatic nerve 3 and 5 d after cut. The graph shows densitometric quantification of blots. Data are presented as mean ± SEM (error bars) from three independent experiments. *, P < 0.05 (sciatic nerves relative to optic nerves); **, P < 0.01 (cut sciatic nerves relative to uncut nerves); n.s., not significant (cut optic nerves relative to uncut nerves).

Mentions: Ceramide has been proposed to act via the JNK/c-Jun pathway to promote autophagy (Ravikumar et al., 2010). We reported previously that c-Jun is a master regulator of the Schwann cell response to injury, and that myelin protein and lipid degradation are delayed in c-Jun cKO mice (Arthur-Farraj et al., 2012). Accordingly, treatment with JNK inhibitor SP600125 strongly inhibited myelin protein breakdown in Schwann cell cultures (Fig. 6, B and C). To test whether the JNK/c-Jun pathway regulated myelinophagy, we examined autophagic flux in nerves from WT mice treated with SP600125 and nerves from WT and c-Jun cKO mice. Autophagic flux was significantly reduced in SP600125-treated and c-Jun cKO nerves (Fig. 7, A and B). This indicates that the JNK/c-Jun pathway is involved in driving Schwann cell autophagy in injured nerves.


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

Gomez-Sanchez JA, Carty L, Iruarrizaga-Lejarreta M, Palomo-Irigoyen M, Varela-Rey M, Griffith M, Hantke J, Macias-Camara N, Azkargorta M, Aurrekoetxea I, De Juan VG, Jefferies HB, Aspichueta P, Elortza F, Aransay AM, Martínez-Chantar ML, Baas F, Mato JM, Mirsky R, Woodhoo A, Jessen KR - J. Cell Biol. (2015)

Regulation of myelinophagy. (A and B) Graph showing reduced LC3 II accumulation in nerve segments (A) maintained in vitro for 5 d and treated with JNK inhibitor in the presence and absence of NH4Cl (3 h treatment) and in nerve segments (B) maintained in vitro for 5 d from cJun cKO mice compared with WT mice, in the presence and absence of NH4Cl (3 h treatment). Graphs show reduced net LC3 II flux. Data are presented as mean ± SEM (error bars) from three independent experiments. **, P < 0.01 (treated cells relative to untreated cells; cJun cKO relative to WT). (C) Western blots showing elevated LC3 II levels in uninjured C3 nerves compared with WT nerves. The graph shows densitometric quantification of blots. n = 3 mice for each genotype. Data are presented as mean ± SEM (error bars). *, P < 0.05 (C3 mice relative to WT). (D) Western blots showing that LC3 II levels in optic nerves are substantially lower than in sciatic nerve 3 and 5 d after cut. The graph shows densitometric quantification of blots. Data are presented as mean ± SEM (error bars) from three independent experiments. *, P < 0.05 (sciatic nerves relative to optic nerves); **, P < 0.01 (cut sciatic nerves relative to uncut nerves); n.s., not significant (cut optic nerves relative to uncut nerves).
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fig7: Regulation of myelinophagy. (A and B) Graph showing reduced LC3 II accumulation in nerve segments (A) maintained in vitro for 5 d and treated with JNK inhibitor in the presence and absence of NH4Cl (3 h treatment) and in nerve segments (B) maintained in vitro for 5 d from cJun cKO mice compared with WT mice, in the presence and absence of NH4Cl (3 h treatment). Graphs show reduced net LC3 II flux. Data are presented as mean ± SEM (error bars) from three independent experiments. **, P < 0.01 (treated cells relative to untreated cells; cJun cKO relative to WT). (C) Western blots showing elevated LC3 II levels in uninjured C3 nerves compared with WT nerves. The graph shows densitometric quantification of blots. n = 3 mice for each genotype. Data are presented as mean ± SEM (error bars). *, P < 0.05 (C3 mice relative to WT). (D) Western blots showing that LC3 II levels in optic nerves are substantially lower than in sciatic nerve 3 and 5 d after cut. The graph shows densitometric quantification of blots. Data are presented as mean ± SEM (error bars) from three independent experiments. *, P < 0.05 (sciatic nerves relative to optic nerves); **, P < 0.01 (cut sciatic nerves relative to uncut nerves); n.s., not significant (cut optic nerves relative to uncut nerves).
Mentions: Ceramide has been proposed to act via the JNK/c-Jun pathway to promote autophagy (Ravikumar et al., 2010). We reported previously that c-Jun is a master regulator of the Schwann cell response to injury, and that myelin protein and lipid degradation are delayed in c-Jun cKO mice (Arthur-Farraj et al., 2012). Accordingly, treatment with JNK inhibitor SP600125 strongly inhibited myelin protein breakdown in Schwann cell cultures (Fig. 6, B and C). To test whether the JNK/c-Jun pathway regulated myelinophagy, we examined autophagic flux in nerves from WT mice treated with SP600125 and nerves from WT and c-Jun cKO mice. Autophagic flux was significantly reduced in SP600125-treated and c-Jun cKO nerves (Fig. 7, A and B). This indicates that the JNK/c-Jun pathway is involved in driving Schwann cell autophagy in injured nerves.

Bottom Line: Myelinophagy was positively regulated by the Schwann cell JNK/c-Jun pathway, a central regulator of the Schwann cell reprogramming induced by nerve injury.We also present evidence that myelinophagy is defective in the injured central nervous system.These results reveal an important role for inductive autophagy during Wallerian degeneration, and point to potential mechanistic targets for accelerating myelin clearance and improving demyelinating disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, England, UK.

Show MeSH
Related in: MedlinePlus