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Nat Neurosci. 2014 Oct;17(10):1351-61. doi: 10.1038/nn.3809. Epub 2014 Sep 7.

Metabolic regulator LKB1 is crucial for Schwann cell-mediated axon maintenance.

Author information

1
Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
2
Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
3
Department of Anesthesiology, Washington University Pain Center, St. Louis, Missouri, USA.
4
Department of Chemistry, Washington University, St. Louis, Missouri, USA.
5
Department of Internal Medicine, Division of Bioorganic Chemistry and Molecular Pharmacology, Washington University School of Medicine, St. Louis, Missouri, USA.
6
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.
7
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.

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.

PMID:
25195104
PMCID:
PMC4494117
DOI:
10.1038/nn.3809
[Indexed for MEDLINE]
Free PMC Article

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