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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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Genetic inactivation of autophagy retards the generation of repair cells after injury in vivo. (A and B) Graph showing fold change of the top 25 down-regulated (A) and up-regulated (B) proteins in 5 d cut nerves relative to uninjured nerves in WT and Atg7 cKO mice from proteomics analysis (Fig. S4 E). n = 5 mice for each genotype. Data are presented as mean ± SEM (error bars). *, P < 0.05 (Atg7 cKO relative to WT). (C) Western blot showing lower levels of the repair Schwann cell marker p75NTR in 5 d cut nerves from Atg7 cKO mice compared with WT controls. The graph shows densitometric analysis of Western blots. n = 3 mice for each genotype. Data are presented as mean ± SEM (error bars). **, P < 0.01. (D) qPCR analysis showing significantly lower levels of the mRNA levels of the repair Schwann cell markers Shh, GDNF, and Olig1 in 2, 5, and 7 d cut nerves from Atg7 cKO mice compared with WT controls. Data are expressed as fold change in cut nerves relative to uncut nerves. n = 3 mice for each genotype/time point. Data are presented as mean ± SEM (error bars). **, P < 0.01 (Atg7 cKO relative to WT).
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fig5: Genetic inactivation of autophagy retards the generation of repair cells after injury in vivo. (A and B) Graph showing fold change of the top 25 down-regulated (A) and up-regulated (B) proteins in 5 d cut nerves relative to uninjured nerves in WT and Atg7 cKO mice from proteomics analysis (Fig. S4 E). n = 5 mice for each genotype. Data are presented as mean ± SEM (error bars). *, P < 0.05 (Atg7 cKO relative to WT). (C) Western blot showing lower levels of the repair Schwann cell marker p75NTR in 5 d cut nerves from Atg7 cKO mice compared with WT controls. The graph shows densitometric analysis of Western blots. n = 3 mice for each genotype. Data are presented as mean ± SEM (error bars). **, P < 0.01. (D) qPCR analysis showing significantly lower levels of the mRNA levels of the repair Schwann cell markers Shh, GDNF, and Olig1 in 2, 5, and 7 d cut nerves from Atg7 cKO mice compared with WT controls. Data are expressed as fold change in cut nerves relative to uncut nerves. n = 3 mice for each genotype/time point. Data are presented as mean ± SEM (error bars). **, P < 0.01 (Atg7 cKO relative to WT).

Mentions: After injury, myelin and nonmyelin (Remak) Schwann cells undergo a c-Jun–dependent reprogramming to form repair Schwann cells (Arthur-Farraj et al., 2012). We examined whether this important cell type conversion was altered in Atg7 cKO nerves using global proteomic analysis. Injury (5 d cut nerves) resulted in substantial changes in the proteomic profile, involving both up- and down-regulation (Fig. S4 E), as described previously (Jiménez et al., 2005). Notably, we found that 12 of the 25 most strongly down-regulated proteins after nerve cut in WT nerves were down-regulated to a significantly lesser degree in Atg7 cKO mice (Fig. 5 A). Conversely, 11 of the 25 most strongly up-regulated proteins in WT nerves were up-regulated to a significantly lesser degree in Atg7 cKO mice (Fig. 5 B). To further confirm that generation of repair Schwann cells was affected in the Atg7 cKO mice, we examined expression of markers associated with these cells after injury (Arthur-Farraj et al., 2012). We found that the expression of p75NTR protein, and of the Shh, GDNF, and Olig1 genes, was significantly reduced in the Atg7 cKO mice (Fig. 5, C and D).


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)

Genetic inactivation of autophagy retards the generation of repair cells after injury in vivo. (A and B) Graph showing fold change of the top 25 down-regulated (A) and up-regulated (B) proteins in 5 d cut nerves relative to uninjured nerves in WT and Atg7 cKO mice from proteomics analysis (Fig. S4 E). n = 5 mice for each genotype. Data are presented as mean ± SEM (error bars). *, P < 0.05 (Atg7 cKO relative to WT). (C) Western blot showing lower levels of the repair Schwann cell marker p75NTR in 5 d cut nerves from Atg7 cKO mice compared with WT controls. The graph shows densitometric analysis of Western blots. n = 3 mice for each genotype. Data are presented as mean ± SEM (error bars). **, P < 0.01. (D) qPCR analysis showing significantly lower levels of the mRNA levels of the repair Schwann cell markers Shh, GDNF, and Olig1 in 2, 5, and 7 d cut nerves from Atg7 cKO mice compared with WT controls. Data are expressed as fold change in cut nerves relative to uncut nerves. n = 3 mice for each genotype/time point. Data are presented as mean ± SEM (error bars). **, P < 0.01 (Atg7 cKO relative to WT).
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fig5: Genetic inactivation of autophagy retards the generation of repair cells after injury in vivo. (A and B) Graph showing fold change of the top 25 down-regulated (A) and up-regulated (B) proteins in 5 d cut nerves relative to uninjured nerves in WT and Atg7 cKO mice from proteomics analysis (Fig. S4 E). n = 5 mice for each genotype. Data are presented as mean ± SEM (error bars). *, P < 0.05 (Atg7 cKO relative to WT). (C) Western blot showing lower levels of the repair Schwann cell marker p75NTR in 5 d cut nerves from Atg7 cKO mice compared with WT controls. The graph shows densitometric analysis of Western blots. n = 3 mice for each genotype. Data are presented as mean ± SEM (error bars). **, P < 0.01. (D) qPCR analysis showing significantly lower levels of the mRNA levels of the repair Schwann cell markers Shh, GDNF, and Olig1 in 2, 5, and 7 d cut nerves from Atg7 cKO mice compared with WT controls. Data are expressed as fold change in cut nerves relative to uncut nerves. n = 3 mice for each genotype/time point. Data are presented as mean ± SEM (error bars). **, P < 0.01 (Atg7 cKO relative to WT).
Mentions: After injury, myelin and nonmyelin (Remak) Schwann cells undergo a c-Jun–dependent reprogramming to form repair Schwann cells (Arthur-Farraj et al., 2012). We examined whether this important cell type conversion was altered in Atg7 cKO nerves using global proteomic analysis. Injury (5 d cut nerves) resulted in substantial changes in the proteomic profile, involving both up- and down-regulation (Fig. S4 E), as described previously (Jiménez et al., 2005). Notably, we found that 12 of the 25 most strongly down-regulated proteins after nerve cut in WT nerves were down-regulated to a significantly lesser degree in Atg7 cKO mice (Fig. 5 A). Conversely, 11 of the 25 most strongly up-regulated proteins in WT nerves were up-regulated to a significantly lesser degree in Atg7 cKO mice (Fig. 5 B). To further confirm that generation of repair Schwann cells was affected in the Atg7 cKO mice, we examined expression of markers associated with these cells after injury (Arthur-Farraj et al., 2012). We found that the expression of p75NTR protein, and of the Shh, GDNF, and Olig1 genes, was significantly reduced in the Atg7 cKO mice (Fig. 5, C and D).

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