Regulation and dysregulation of axon infrastructure by myelinating glia

3903 The Rockefeller University Press J. Cell Biol. Vol. 216 No. 12 3903–3916 https://doi.org/10.1083/jcb.201702150 Introduction Multiple sclerosis (MS) is canonically described as a demyelinating disease, yet the most severe clinical outcomes in MS patients are associated not with demyelination itself but with its eventual sequelae: axon loss and neurodegeneration. Although inflammatory injury has been proposed as a primary determinant of axonal damage, immunosuppressive therapies have had limited success in preventing the onset of progressive MS, which is characterized by worsening, permanent neurological disability and chronically demyelinated lesions with relatively sparse immune infiltration and profound axon loss (Bjartmar et al., 2003; Trapp and Nave, 2008; Dutta and Trapp, 2011; Hauser et al., 2017). Charcot–Marie–Tooth disease type 1, an inherited demyelinating peripheral neuropathy resulting from mutations in Schwann cell myelin genes, also involves progressive axon loss with a nonimmune etiology (Suter and Scherer, 2003; Nave et al., 2007). These clinical observations and histopathological findings, along with the intimate physical and molecular association of the axon and its myelinating glia, suggest a situation in which axonal integrity is maintained by the presence of myelin. However, the lack of adequate animal models to study demyelination in isolation has presented significant barriers toward defining these interactions. Consequently, the mechanisms of secondary degeneration in a demyelinated axon, and even the underlying assumption that the loss of myelin is detrimental to the axon, remain patently unclear. Several mouse mutants harboring mutations in myelinassociated genes exhibit late-onset axon degeneration in the absence of inflammatory demyelination, prompting a search for basic biological mechanisms through which oligodendrocytes support axon function (Griffiths et al., 1998; Yin et al., 1998; Lappe-Siefke et al., 2003). Recent attention has been focused on the hypothesis that myelinating glia provide metabolic support to their invested axons, centered on the observation that oligodendrocyte-derived glycolytic metabolites trafficked by monocarboxylate transporter 1 can be metabolized by myelinated axons. In support of this, down-regulation of monocarboxylate transporter 1 specifically in oligodendrocytes is sufficient to impair long-term maintenance of myelinated axons, and oligodendrocytes have the capacity to sense and respond to axonal energetic demand through N-Methyl-d-aspartate receptor signaling (Fünfschilling et al., 2012; Lee et al., 2012; Saab et al., 2016). Despite these seminal observations, the significance of metabolic support has not been demonstrated in the context of demyelination, and it is conceivable that metabolic support by myelinating glia does not comprehensively account for all axonal damage that occurs in myelin disease. Properties of axonal infrastructure that are established or regulated during myelination, such as the maturation of the cytoskeleton, trafficking of cargoes, and nodal organization of voltage-gated ion channels, are perturbed or reversed during demyelination. As axon integrity is contingent on the proper functioning of these processes, their disruption may serve as a unifying model of secondary axon degeneration, onto which pathological events, such as the loss of metabolic and ion homeostasis, converge (Hirokawa et al., 2010; Kevenaar and Hoogenraad, 2015; Zhang and Rasband, 2016). Interrogating the mechanisms of injury in a demyelinated axon then becomes a question of understanding the fundamental cell biology of the axon–myelin unit. To this end, recent advances using in vivo two-photon imaging, high-pressure freezing electron microscopy, superresolution microscopy, and protein crystallography offer intricate descriptions of axon– glia interactions (Nikić et al., 2011; Xu et al., 2013; Sorbara et al., 2014; Pronker et al., 2016; D’Este et al., 2017; Snaidero et al., 2017). These new insights, and others, are examined in Axon loss and neurodegeneration constitute clinically debilitating sequelae in demyelinating diseases such as multiple sclerosis, but the underlying mechanisms of secondary degeneration are not well understood. Myelinating glia play a fundamental role in promoting the maturation of the axon cytoskeleton, regulating axon trafficking parameters, and imposing architectural rearrangements such as the nodes of Ranvier and their associated molecular domains. In the setting of demyelination, these changes may be reversed or persist as maladaptive features, leading to axon degeneration. In this review, we consider recent insights into axon–glial interactions during development and disease to propose that disruption of the cytoskeleton, nodal architecture, and other components of axon infrastructure is a potential mediator of pathophysiological damage after demyelination. Regulation and dysregulation of axon infrastructure by myelinating glia