Metabolic Interaction Between Schwann Cells and Axons Under Physiological and Disease Conditions

Abstract

Recent research into axon-glial interactions in the nervous system has made a compelling case that glial cells have a relevant role in the metabolic support of axons, and that, in the case of myelinating cells, this role is independent of myelination itself. In this mini-review article, we summarize some of those observations and focus on Schwann cells (SC), drawing parallels between glia of the central and peripheral nervous systems (PNS), pointing out limitations in current knowledge, and discussing its potential clinical relevance. First, we introduce SC, their development and main roles, and follow with an evolutionary perspective of glial metabolic function. Then we provide evidence of the myelin-independent aspects of axonal support and their coupling to neuronal metabolism. Finally, we address the opportunity to use SC-axon metabolic interactions as therapeutic targets to treat peripheral neuropathies.

How Does Protein Zero Assemble Compact Myelin?

“…Myelin is required for axonal saltatory conduction in the central and peripheral nervous systems (CNS and PNS, respectively) of vertebrates [1]. While involved in the structural and trophic support of the axon itself [2][3][4][5], the insulative character of myelin arises from a highly specialized plasma membrane, which is wrapped around selected axonal segments through a mechanism powered by actin disassembly [6]. After several dozen wraps, myelin-specific proteins trigger compaction of myelin, forming a highly periodic lipid-rich structure with very low water content of only~40% of the total myelin mass [7][8][9].…”

More Than Mortar: Glia as Architects of Nervous System Development and Disease

“…This role of glia was first described in the honeybee retina (Tsacopoulos and Poitry, 1982;Tsacopoulos et al, 1987Tsacopoulos et al, , 1988 and later for Müller glia in the rodent retina (Poitry-Yamate and Tsacopoulos, 1992;Poitry-Yamate et al, 1995). This process converges on a glia-toneuron lactate shuttle following glycolysis, regardless of system (invertebrate vs. vertebrate) or cell type (Fünfschilling et al, 2012;Lee et al, 2012;Beirowski et al, 2014;Pooya et al, 2014;Volkenhoff et al, 2015;Saab et al, 2016;Philips and Rothstein, 2017;Delgado et al, 2018;Yildirim et al, 2019;Deitmer et al, 2019;Bouçanova and Chrast, 2020). Astrocytes, which form an integral component of the neurovascular unit, are also known to shuttle lactate to neurons in both animal models and in the human brain (Pellerin and Magistretti, 1994;Svichar and Chesler, 2003;Mangia et al, 2009;Deitmer et al, 2019).…”

“…In CNS white matter and in peripheral nerves, metabolic support of axons is carried out by myelinating oligodendrocytes and Schwann cells, respectively (Fünfschilling et al, 2012;Philips and Rothstein, 2017;Bouçanova and Chrast, 2020). The myelin sheath is organized into multiple functional domains, including cytoplasmic (myelinic) channels that facilitate uptake of metabolites and ions from neighboring astrocytes (for oligodendrocytes) or from the environment (both oligodendrocytes and Schwann cells), which can then be transferred to the associated axonal segment (Lutz et al, 2009;Salzer, 2015;Snaidero et al, 2017).…”

“…The myelin sheath is organized into multiple functional domains, including cytoplasmic (myelinic) channels that facilitate uptake of metabolites and ions from neighboring astrocytes (for oligodendrocytes) or from the environment (both oligodendrocytes and Schwann cells), which can then be transferred to the associated axonal segment (Lutz et al, 2009;Salzer, 2015;Snaidero et al, 2017). Given that mutations in many genes enriched in myelinating glia (e.g., PLP, CNPase, and MPZ) cause axonal degeneration in the absence of overt dysmyelination (Philips and Rothstein, 2017;Bouçanova and Chrast, 2020), this function of oligodendrocytes and Schwann cells is distinct from the role of myelin in saltatory conduction (discussed below in section "Myelination and Circuit Function"). In the CNS, oligodendrocytes take in extracellular glucose, which is then converted to lactate and transferred to neurons via the monocarboxylate transporter MCT1 (Lee et al, 2012).…”

Cellular mechanisms of heterogeneity inNF2-mutant schwannoma

“…Rather than the discrete junctional and fluid-exposed apical surfaces of conventional epithelia, apicobasally polarized SCs form a hybrid 'apicojunctional' adaxonal surface that is dedicated to contacting the nerve and enriched in both apical and cell-cell adhesion proteins [15][16][17][18] . The SC:axon interface is also a crucial site of metabolic communication between the two cell types 19 . The remaining abaxonal surface contacts self-generated basal lamina.…”