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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / physiology*
  • Cells, Cultured
  • Deoxyglucose / metabolism
  • Female
  • In Vitro Techniques
  • Luminescent Proteins / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Activity / genetics
  • Mutation / genetics
  • Myelin P0 Protein / genetics
  • Myelin Proteolipid Protein / genetics
  • Nerve Fibers, Myelinated / metabolism*
  • Neuromuscular Junction / cytology
  • Neurons / physiology
  • Peripheral Nerves / cytology
  • Peripheral Nerves / physiology
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Schwann Cells / physiology*

Substances

  • Luminescent Proteins
  • Myelin P0 Protein
  • Myelin Proteolipid Protein
  • Plp1 protein, mouse
  • Deoxyglucose
  • Stk11 protein, mouse
  • Protein-Serine-Threonine Kinases

Associated data

  • GEO/GSE60325