Similarities between Inherited Demyelinating Neuropathies and Wallerian Degeneration

Abstract

Wallerian degeneration (WD) and inherited demyelinating neuropathies of the Charcot-Marie-Tooth type 1 (CMT1) appear to represent completely distinct events. CMT1-like diseases are chronic disorders of peripheral nerves that are genetically caused and lead to secondary neurodegenerative events, resulting in usually non-treatable disabilities, whereas WD is an acute, usually transient, reaction on injuries, aiming to allow peripheral nerve regeneration. Despite these differences, there are some striking similarities regarding molecular characteristics of neural cells in the affected peripheral nerves. The most conspicuous similarities might comprise the inflammatory component in both situations, as identified in appropriate mouse models. However, although inflammation is a beneficial component in WD, leading to removal of regrowth-repellent myelin debris, inflammation in CMT1 mouse models causes damage of initially intact nerve fibers. We hypothesize that, in CMT1 models, molecular pathways are activated that are shared with an important repair program after peripheral nerve injury, but lead to neural perturbation when activated under nonlesion conditions, as is the case in CMT1. These novel insights into the pathogenesis of CMT1 might be instrumental for the development of new therapeutic options in humans.

The leptin receptor mutation of the obese Zucker rat causes sciatic nerve demyelination with a centripetal pattern defect

“…Excess of ceramides can result in a sort of Wallerian degeneration. 109,111,116,225 However, the Wallerian degenerative morphology does not fit with the type of injuries found here since axons are not segmented 226 and the described injuries do not compare with other recent diabetes findings. 227 Additionally, traumatic crush defects found in a recent ultrastructural study, dealing with sciatic nerve in rodent, are different than our data.…”

“…Other interactions exist between lipid rafts and ceramide or sphingomyelin precursors due to external glycanized moieties [225][226][227] and other membrane glycolipids. 224 Even though these plasmalogens belong to the family of immunoglobulins and can provide with injuries potent antigens toward autoimmune myelin defects akin to those noted in CNS (e.g.…”

Schwann cell dedifferentiation-associated demyelination leads to exocytotic myelin clearance in inflammatory segmental demyelination

“…In addition, reactive SC changes due to the activation of ErbB2 signaling, a presumptive mechanism implicated in injury-induced SAD (Guertin et al, 2005), were reported to be involved in leprotic demyelination (Tapinos, Ohnishi, & Rambukkana., 2006). Moreover, demyelinating neuropathies due to Pmp22 over-expression or connexin 32 deficiency exhibited dedifferentiated SC phenotypes with demyelination (Martini et al, 2013;Klein, Groh, Wettmarshausen, & Martini, 2014). Interestingly, although these are not inflammatory diseases, many of them are related to the appearance of myelindigesting macrophages in demyelinating nerves (Groh et al, 2015).…”

“…Interestingly, this SC dedifferentiation-associated demyelination (SAD) is likely to participate in other forms of demyelinating conditions with intact axons. For example, the induction of markers for SC dedifferentiation such as c-Jun and p75 neurotrophin receptor (p75Ngfr) was found in inflammatory and hereditary demyelinating neuropathies in animals and humans (Hutton et al, 2011;Jang et al, 2016;Martini, Klein, & Groh, 2013). It has also been shown that SC autophagy is activated during demyelination in a mouse model of IDN and tellurium-induced demyelination (Calle, Berciano, Fern andez, & Lafarga, 1999;Jang et al, 2016).…”

Progressive Degeneration and Inhibition of Peripheral Nerve Regeneration in the SOD1-G93A Mouse Model of Amyotrophic Lateral Sclerosis

“…Wallerian degeneration, a process in which the axon and myelin degenerate, is a cellular response activated by the injured axon accompanied by dedifferentiation of Schwann cells (SC) [20, 21]. Immune cells are recruited to the injured nerve to remove myelin fragments and promote axon regeneration and SC remyelination to restore motor function [19].…”