The Influence of Schwann Cell Metabolism and Dysfunction on Axon Maintenance

Abstract

Schwann cells are the glial cells in the peripheral nervous system responsible for the production of myelin, which is essential for rapid, saltatory conduction in nerves. However, it has become increasingly recognized that Schwann cells are also key regulators of neuron viability and function, especially for sensory neurons. Neurons and Schwann cells form a tightknit, interdependent couple with complex mechanisms of communication that are only beginning to be understood. There is growing evidence that Schwann cell metabolism profoundly influences axons through the release of a variety of metabolites. These glial cells serve as energy depots for axon function, supplying lactate and/or pyruvate during repeated firing and after injury. Lipid metabolism in Schwann cells, which is critical for myelin production, also affects axon viability, such that disruptions in the production or breakdown of lipids can lead to axon dysfunction and subsequent degeneration. Here, we discuss emerging concepts on the mechanisms by which Schwann cell metabolites influence neuron activity and survival, with particular focus on how dysfunction of lipid metabolism can lead to axon degeneration and the development of peripheral neuropathy.

Keywords: Schwann cell; axon; myelin.

FIGURE 1

Schwann cells may provide trophic support for neurons prior to final target innervation. Neurotrophic factors derived from Schwann cells and target organs are shuttled to the neuron soma via retrograde axonal transport to promote survival. Loss of Schwann cells or disruption of their axon association results in reduced trophic signaling, leading to degeneration.

FIGURE 2

Destabilization of membrane functions by neurotoxic lipids. Disrupting the delicate balance of lipid composition through deficiency in key lipid species (e.g., plasmalogens (shown in teal)), oxidative modification of lipids, or incorporation of cytotoxic lipids can alter membrane fluidity and permeability, thereby disrupting lipid rafts, which are major centers for vital processes such as signal transduction, nutrient transport, and cell‐to‐cell communication, contributing to neurodegenerative conditions. (CHO, cholesterol).

FIGURE 3

Initiation of oxidative stress by cytotoxic lipids contributes to ROS generation and lipid peroxidation. Oxidative stress begins when harmful cytotoxic lipids trigger reactions that produce reactive oxygen species (ROS). These reactive molecules can damage cellular structures like proteins, DNA, and lipids. This leads to lipid peroxidation, where the lipids in cell membranes are oxidized, compromising their integrity and functionality. This cycle exacerbates cellular damage, potentially resulting in axon degeneration and cell death.

FIGURE 4

The buildup of harmful lipids like di‐ and triacylglycerides (DAGs and TAGs) or fatty acids, like palmitate, causes a disturbance in energy metabolism, ultimately leading to the deterioration of axons. DAGs and TAGs can activate protein kinase C (PKC), which phosphorylates and inhibits components of the insulin receptor signaling pathway, causing reduced glucose metabolism and, ultimately, axon degeneration. Certain lipids, such as palmitate, can suppress the production of NAD+, resulting in SARM1 activation, which results in axon degeneration.

FIGURE 5

Certain lipids, particularly ceramides, can act as signaling molecules that stimulate pathways promoting neurodegeneration. As ceramides accumulate, they can stimulate inflammatory pathways, such as NF‐κB, the stress kinase JNK, which can activate caspases, and damage mitochondria, leading to the production of reactive oxygen species (ROS) and the release of cytochrome C, further activating caspases. These pathways all ultimately promote axon degeneration.

FIGURE 6

Cytotoxic lipids can disrupt the delicate balance of axonal transport. These damaging molecules can disrupt transport either directly, by altering the function of the motor proteins dynein and kinesin, or indirectly, by impairing mitochondrial function and energy generation. Preventing axonal transport leads to a breakdown in cellular communication and function, resulting in axon degeneration and cell death.

FIGURE 7

Altered neuronal conduction and signaling can result from lipid‐induced dysregulation of ion channels. Cytotoxic lipids can disrupt Na⁺ and/or K⁺ channels, leading to excitotoxicity. Some lipids impair the Na⁺/K⁺ ATPase, resulting in excess Ca²⁺, which can also occur through impairment of Ca²⁺ channels. High levels of Ca²⁺ activate proteases and phospholipases, ultimately causing axon degeneration.

FIGURE 8

Outline of sphingolipid metabolism and the metabolic steps that were found to be associated with peripheral neuropathies. Cer, ceramide; CMT, Charcot–Marie–Tooth disease; (dh)SM, (dihydro)Sphingomyelin; FA, fatty acids; FD, Fabry disease; GalCer, galactosyl ceramide; GBS, Guillain–Barre syndrome; GD3, disialogangliosides; GluCer, glucosylceramide; GM3, monosialogangliosides; GT3, tetrasialogangliosides; HSAN1, hereditary sensory and autonomic neuropathy; LacCer, lactosylceramide; LD with PNP, leukodystrophy with purine nucleoside phosphorylase deficiency; S1P, sphingosine 1‐phosphate; SPT, serine‐palmitoyl transferase; T2DM, type 2 diabetes mellitus; TG, triglycerides [adapted from (Hornemann 2021)].