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

被引:152
作者
Beirowski, Bogdan [1 ]
Babetto, Elisabetta [2 ]
Golden, Judith P. [3 ]
Chen, Ying-Jr [4 ]
Yang, Kui [5 ]
Gross, Richard W. [5 ]
Patti, Gary J. [1 ,4 ,5 ]
Milbrandt, Jeffrey [1 ,6 ]
机构
[1] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO 63110 USA
[3] Washington Univ, Pain Ctr, Dept Anesthesiol, St Louis, MO 63110 USA
[4] Washington Univ, Dept Chem, St Louis, MO 63110 USA
[5] Washington Univ, Sch Med, Dept Internal Med, Div Bioorgan Chem & Mol Pharmacol, St Louis, MO 63110 USA
[6] Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA
基金
美国国家卫生研究院;
关键词
ACTIVATED PROTEIN-KINASE; HEMATOPOIETIC STEM-CELLS; DIABETIC-NEUROPATHY; ENERGY HOMEOSTASIS; AMPK; PATHWAY; MTOR; MYELINATION; SUPPORT; NEURONS;
D O I
10.1038/nn.3809
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:1351 / 1361
页数:11
相关论文
共 50 条
[1]   c-Jun Reprograms Schwann Cells of Injured Nerves to Generate a Repair Cell Essential for Regeneration [J].
Arthur-Farraj, Peter J. ;
Latouche, Morwena ;
Wilton, Daniel K. ;
Quintes, Susanne ;
Chabrol, Elodie ;
Banerjee, Annbily ;
Woodhoo, Ashwin ;
Jenkins, Billy ;
Rahman, Mary ;
Turmaine, Mark ;
Wicher, Grzegorz K. ;
Mitter, Richard ;
Greensmith, Linda ;
Behrens, Axel ;
Raivich, Gennadij ;
Mirsky, Rhona ;
Jessen, Kristjan R. .
NEURON, 2012, 75 (04) :633-647
[2]   LKB1 and SAD kinases define a pathway required for the polarization of cortical neurons [J].
Barnes, Anthony P. ;
Lilley, Brendan N. ;
Pan, Y. Albert ;
Plummer, Lisa J. ;
Powell, Ashton W. ;
Raines, Alexander N. ;
Sanes, Joshua R. ;
Polleux, Franck .
CELL, 2007, 129 (03) :549-563
[3]   Concepts for regulation of axon integrity by enwrappin gglia [J].
Beirowski, Bogdan .
FRONTIERS IN CELLULAR NEUROSCIENCE, 2013, 7
[4]   Primary cilia regulate mTORC1 activity and cell size through Lkb1 [J].
Boehlke, Christopher ;
Kotsis, Fruzsina ;
Patel, Vishal ;
Braeg, Simone ;
Voelker, Henriette ;
Bredt, Saskia ;
Beyer, Theresa ;
Janusch, Heike ;
Hamann, Christoph ;
Goedel, Markus ;
Mueller, Klaus ;
Herbst, Martin ;
Hornung, Miriam ;
Doerken, Mara ;
Koettgen, Michael ;
Nitschke, Roland ;
Igarashi, Peter ;
Walz, Gerd ;
Kuehn, E. Wolfgang .
NATURE CELL BIOLOGY, 2010, 12 (11) :1115-U126
[5]   The regulation and function of mammalian AMPK-related kinases [J].
Bright, N. J. ;
Thornton, C. ;
Carling, D. .
ACTA PHYSIOLOGICA, 2009, 196 (01) :15-26
[6]   The regulation of AMP-activated protein kinase by upstream kinases [J].
Carling, D. ;
Sanders, M. J. ;
Woods, A. .
INTERNATIONAL JOURNAL OF OBESITY, 2008, 32 (Suppl 4) :S55-S59
[7]   The role of aberrant mitochondrial bioenergetics in diabetic neuropathy [J].
Chowdhury, Subir K. Roy ;
Smith, Darrell R. ;
Fernyhough, Paul .
NEUROBIOLOGY OF DISEASE, 2013, 51 :56-65
[8]   Nutrient excess and altered mitochondrial proteome and function contribute to neurodegeneration in diabetes [J].
Chowdhury, Subir K. Roy ;
Dobrowsky, Rick T. ;
Femyhough, Paul .
MITOCHONDRION, 2011, 11 (06) :845-854
[9]   Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models [J].
Chrast, Roman ;
Saher, Gesine ;
Nave, Klaus-Armin ;
Verheijen, Mark H. G. .
JOURNAL OF LIPID RESEARCH, 2011, 52 (03) :419-434
[10]   Loss of Lkb1 provokes highly invasive endometrial adenocarcinomas [J].
Contreras, Cristina M. ;
Gurumurthy, Sushma ;
Haynie, J. Marshall ;
Shirley, Lane J. ;
Akbay, Esra A. ;
Wingo, Shana N. ;
Schorge, John O. ;
Broaddus, Russell R. ;
Wong, Kwok-Kin ;
Bardeesy, Nabeel ;
Castrillon, Diego H. .
CANCER RESEARCH, 2008, 68 (03) :759-766