Editors' ChoiceNeuroscience

Degeneration Without Demyelination

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Science Signaling  07 Oct 2014:
Vol. 7, Issue 346, pp. ec276
DOI: 10.1126/scisignal.2005998

Neurons rely on glia for support, protection, and survival. In the central nervous system, oligodendrocytes provide metabolic intermediates that are necessary for axonal function. Bierowski et al. reported that the metabolism of both myelinating and nonmyelinating Schwann cells is also important for axon support in the peripheral nervous system (PNS). Liver kinase B1 (LKB1) is a serine-threonine kinase that controls carbohydrate, protein, and lipid metabolism, in part by activating the kinase AMPK, which represses signaling through the mechanistic target of rapamycin (mTOR). Mice lacking LKB1 specifically in Schwann cells (LKB1-SCKO mice) exhibited delayed glial differentiation and myelination, thinner myelin sheaths, and reduced sciatic nerve conduction velocity. As they aged, the animals gradually developed peripheral neuropathy, and both myelinated and unmyelinated axons of the sciatic and femoral nerves degenerated without neuronal cell death. The myelination defects in the mutant Schwann cells were not responsible for the neuronal degeneration, because knocking out Lkb1 in Schwann cells only after they had matured did not affect myelination or nerve conduction velocities, but nevertheless caused axonal degeneration. Axonal degeneration preferentially affected small-diameter nonmyelinated sensory neurons, similar to diabetic neuropathy to which high circulating glucose may contribute (see commentary by Tzvetanova and Nave). Metabolomic analysis of extracts of sciatic nerves, which contain both neuronal and glial components, from LKB1-SCKO and control mice revealed changes in the abundance of over 700 metabolites. LKB1-SCKO Schwann cells also had greater numbers of mitochondria and reduced lipid synthesis compared to control cells. Activating AMPK signaling in Schwann cells did not phenocopy loss of LKB1, and inhibiting mTOR signaling did not rescue axonal degeneration in LKB1-SCKO mice, implying that other targets mediate the effects of LKB1 on axon maintenance. Thus, Schwann cell metabolism is important for the health of PNS neurons, perhaps by providing metabolites that would otherwise take a long time to move into the axon from the distant cell body or by supporting the production of signals that promote axonal maintenance.

B. Beirowski, E. Babetto, J. P. Golden, Y. -J. Chen, K. Yang, R. W. Gross, G. J. Patti, J. Milbrandt, Metabolic regulator LKB1 is crucial for Schwann cell–mediated axon maintenance. Nat. Neurosci. 17, 1351–1361 (2014). [PubMed]

I. D. Tzvetanova, K.-A. Nave, Axons hooked to Schwann cell metabolism. Nat. Neurosci. 17, 1293–1295 (2014). [PubMed]

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