title: Metabolic regulator LKB1 is crucial for Schwann cell-mediated axon maintenance.
abstract: Schwann cells (SCs) promote axonal integrity independently of myelination by poorly understood mechanisms. Current models suggest that SC metabolism is critical for this support function and that SC metabolic deficits may lead to axonal demise. The LKB1-AMP-activated protein kinase (AMPK) kinase pathway targets several downstream effectors, including mammalian target of rapamycin (mTOR), and is a key metabolic regulator implicated in metabolic diseases. We found through molecular, structural and behavioral characterization of SC-specific mutant mice that LKB1 activity is central to axon stability, whereas AMPK and mTOR in SCs are largely dispensable. The degeneration of axons in LKB1 mutants was most dramatic in unmyelinated small sensory fibers, whereas motor axons were comparatively spared. LKB1 deletion in SCs led to abnormalities in nerve energy and lipid homeostasis and to increased lactate release. The latter acts in a compensatory manner to support distressed axons. LKB1 signaling is essential for SC-mediated axon support, a function that may be dysregulated in diabetic neuropathy.
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Beirowski
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Babetto
authors.affiliation: Department of Anesthesiology, Washington University Pain Center, St. Louis, Missouri, USA.
authors.forename: Judith P
authors.initials: JP
authors.lastname: Golden
authors.affiliation: Department of Chemistry, Washington University, St. Louis, Missouri, USA.
authors.forename: Ying-Jr
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, Division of Bioorganic Chemistry and Molecular Pharmacology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Kui
authors.identifier: 0000000287603298
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, Division of Bioorganic Chemistry and Molecular Pharmacology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Gross
authors.affiliation: 1] Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA. [2] Department of Chemistry, Washington University, St. Louis, Missouri, USA. [3] Department of Internal Medicine, Division of Bioorganic Chemistry and Molecular Pharmacology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Patti
authors.affiliation: 1] Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA. [2] Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Milbrandt
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D001369:Axons / Q000502:physiology*; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics; D018993:Myelin P0 Protein / Q000235:genetics; D018991:Myelin Proteolipid Protein / Q000235:genetics; D009413:Nerve Fibers, Myelinated / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000166:cytology; D009474:Neurons / Q000502:physiology; D010525:Peripheral Nerves / Q000166:cytology / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012583:Schwann Cells / Q000502:physiology*
chemical_list: D008164:Luminescent Proteins; D018993:Myelin P0 Protein; D018991:Myelin Proteolipid Protein; C047516:Plp1 protein, mouse; D003847:Deoxyglucose; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases