title: Schwann cell autophagy, myelinophagy, initiates myelin clearance from injured nerves.
abstract: Although Schwann cell myelin breakdown is the universal outcome of a remarkably wide range of conditions that cause disease or injury to peripheral nerves, the cellular and molecular mechanisms that make Schwann cell-mediated myelin digestion possible have not been established. We report that Schwann cells degrade myelin after injury by a novel form of selective autophagy, myelinophagy. Autophagy was up-regulated by myelinating Schwann cells after nerve injury, myelin debris was present in autophagosomes, and pharmacological and genetic inhibition of autophagy impaired myelin clearance. 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.
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, England, UK.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Gomez-Sanchez
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, England, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Carty
authors.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Bizkaia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Iruarrizaga-Lejarreta
authors.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Bizkaia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Palomo-Irigoyen
authors.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Bizkaia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Varela-Rey
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, England, UK.
authors.forename: Megan
authors.initials: M
authors.lastname: Griffith
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, England, UK.
authors.forename: Janina
authors.initials: J
authors.lastname: Hantke
authors.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Bizkaia, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Macias-Camara
authors.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Bizkaia, Spain ProteoRed-ISCIII.
authors.forename: Mikel
authors.initials: M
authors.lastname: Azkargorta
authors.affiliation: Department of Physiology, Faculty of Medicine and Dentistry, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain Biocruces Health Research Institute, 48903 Barakaldo, Spain.
authors.forename: Igor
authors.initials: I
authors.lastname: Aurrekoetxea
authors.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Bizkaia, Spain.
authors.forename: Virginia Gutiérrez
authors.initials: VG
authors.lastname: De Juan
authors.affiliation: The Francis Crick Institute, Lincoln's Inn Fields Laboratory, London WC2A 3LY, England, UK.
authors.forename: Harold B J
authors.initials: HB
authors.lastname: Jefferies
authors.affiliation: Department of Physiology, Faculty of Medicine and Dentistry, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain Biocruces Health Research Institute, 48903 Barakaldo, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Aspichueta
authors.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Bizkaia, Spain ProteoRed-ISCIII.
authors.forename: Félix
authors.initials: F
authors.lastname: Elortza
authors.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Bizkaia, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Aransay
authors.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Bizkaia, Spain Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), E-48080 Bilbao, Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: Martínez-Chantar
authors.affiliation: Department of Genome Analysis, Academic Medical Centre, 1105 AZ Amsterdam, Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
authors.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Bizkaia, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, England, UK.
authors.forename: Rhona
authors.initials: R
authors.lastname: Mirsky
authors.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Bizkaia, Spain Ikerbasque, Basque Foundation for Science, 48011 Bilbao, Spain awoodhoo@cicbiogune.es k.jessen@ucl.ac.uk.
authors.forename: Ashwin
authors.initials: A
authors.lastname: Woodhoo
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, England, UK awoodhoo@cicbiogune.es k.jessen@ucl.ac.uk.
authors.forename: Kristján R
authors.initials: KR
authors.lastname: Jessen
mesh_terms: D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D050356:Lipid Metabolism; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000473:pathology* / Q000502:physiology; D059348:Peripheral Nerve Injuries / Q000201:enzymology / Q000473:pathology*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012584:Sciatic Nerve / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014855:Wallerian Degeneration / Q000473:pathology
chemical_list: D016755:Proto-Oncogene Proteins c-jun; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases