PMID- 25195104
OWN - NLM
STAT- MEDLINE
DCOM- 20141121
LR  - 20230711
IS  - 1546-1726 (Electronic)
IS  - 1097-6256 (Print)
IS  - 1097-6256 (Linking)
VI  - 17
IP  - 10
DP  - 2014 Oct
TI  - Metabolic regulator LKB1 is crucial for Schwann cell-mediated axon maintenance.
PG  - 1351-61
LID - 10.1038/nn.3809 [doi]
AB  - 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.
FAU - Beirowski, Bogdan
AU  - Beirowski B
AD  - Department of Genetics, Washington University School of Medicine, St. Louis, 
      Missouri, USA.
FAU - Babetto, Elisabetta
AU  - Babetto E
AD  - Department of Developmental Biology, Washington University School of Medicine, 
      St. Louis, Missouri, USA.
FAU - Golden, Judith P
AU  - Golden JP
AD  - Department of Anesthesiology, Washington University Pain Center, St. Louis, 
      Missouri, USA.
FAU - Chen, Ying-Jr
AU  - Chen YJ
AD  - Department of Chemistry, Washington University, St. Louis, Missouri, USA.
FAU - Yang, Kui
AU  - Yang K
AUID- ORCID: 0000000287603298
AD  - Department of Internal Medicine, Division of Bioorganic Chemistry and Molecular 
      Pharmacology, Washington University School of Medicine, St. Louis, Missouri, USA.
FAU - Gross, Richard W
AU  - Gross RW
AD  - Department of Internal Medicine, Division of Bioorganic Chemistry and Molecular 
      Pharmacology, Washington University School of Medicine, St. Louis, Missouri, USA.
FAU - Patti, Gary J
AU  - Patti GJ
AD  - 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.
FAU - Milbrandt, Jeffrey
AU  - Milbrandt J
AD  - 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.
LA  - eng
SI  - GEO/GSE60325
GR  - P30 NS057105/NS/NINDS NIH HHS/United States
GR  - R01 NS040745/NS/NINDS NIH HHS/United States
GR  - RF1 AG013730/AG/NIA NIH HHS/United States
GR  - R01 AG013730/AG/NIA NIH HHS/United States
GR  - R21NS059566/NS/NINDS NIH HHS/United States
GR  - 2P01 HL057278/HL/NHLBI NIH HHS/United States
GR  - R56 AG013730/AG/NIA NIH HHS/United States
GR  - P30 DK020579/DK/NIDDK NIH HHS/United States
GR  - P01 HL057278/HL/NHLBI NIH HHS/United States
GR  - R21 NS059566/NS/NINDS NIH HHS/United States
GR  - NS087306/NS/NINDS NIH HHS/United States
GR  - AG13730/AG/NIA NIH HHS/United States
GR  - AG0 038036/AG/NIA NIH HHS/United States
GR  - L30 AG038036/AG/NIA NIH HHS/United States
GR  - NS040745/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140907
PL  - United States
TA  - Nat Neurosci
JT  - Nature neuroscience
JID - 9809671
RN  - 0 (Luminescent Proteins)
RN  - 0 (Myelin P0 Protein)
RN  - 0 (Myelin Proteolipid Protein)
RN  - 0 (Plp1 protein, mouse)
RN  - 9G2MP84A8W (Deoxyglucose)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Stk11 protein, mouse)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
CIN - Nat Rev Neurosci. 2014 Nov;15(11):698-9. PMID: 25248331
CIN - Nat Neurosci. 2014 Oct;17(10):1293-5. PMID: 25254976
MH  - AMP-Activated Protein Kinases
MH  - Animals
MH  - Axons/*physiology
MH  - Cells, Cultured
MH  - Deoxyglucose/metabolism
MH  - Female
MH  - In Vitro Techniques
MH  - Luminescent Proteins/genetics
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Motor Activity/genetics
MH  - Mutation/genetics
MH  - Myelin P0 Protein/genetics
MH  - Myelin Proteolipid Protein/genetics
MH  - Nerve Fibers, Myelinated/*metabolism
MH  - Neuromuscular Junction/cytology
MH  - Neurons/physiology
MH  - Peripheral Nerves/cytology/physiology
MH  - Protein Serine-Threonine Kinases/genetics/*metabolism
MH  - Schwann Cells/*physiology
PMC - PMC4494117
MID - NIHMS688841
COIS- Competing financial interest R.W.G. has financial relationships with LipoSpectrum 
      and Platomics Inc. The other authors declare no competing financial interests.
EDAT- 2014/09/10 06:00
MHDA- 2014/12/15 06:00
PMCR- 2015/07/07
CRDT- 2014/09/08 06:00
PHST- 2014/06/24 00:00 [received]
PHST- 2014/08/15 00:00 [accepted]
PHST- 2014/09/08 06:00 [entrez]
PHST- 2014/09/10 06:00 [pubmed]
PHST- 2014/12/15 06:00 [medline]
PHST- 2015/07/07 00:00 [pmc-release]
AID - nn.3809 [pii]
AID - 10.1038/nn.3809 [doi]
PST - ppublish
SO  - Nat Neurosci. 2014 Oct;17(10):1351-61. doi: 10.1038/nn.3809. Epub 2014 Sep 7.