Axonal domain disorganization in Caspr1 and Caspr2 mutant myelinated axons affects neuromuscular junction integrity, leading to muscle atrophy

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The transmission of nerve impulses to distant targets in a fast and efficient manner requires myelination of axons by glial cells. Myelinating Schwann cells in the PNS and oligodendrocytes in the CNS tightly wrap their membranes around axons to form compact myelin to allow establishment of highly organized molecular domains along axons, which include the nodes of Ranvier, paranodes (PN), juxtaparanodes (JPN), and internodes (IN) (Sherman and Brophy, 2005; Buttermore et al., 2013). Each of these domains is assembled with distinct molecular complexes; furthermore, perturbations that alter the structure and function of the nerves or the myelinating glial cells affect axonal integrity, leading to various neuropathologies (Waxman, 2000, 2006; Suter and Scherer, 2003). Progressive muscle wasting and sensory deficits are common features for the heterogeneous group of disorders termed peripheral neuropathies, caused by an inability of affected axons to deliver signals to the target muscles and to transmit sensory information from the periphery back to the CNS (Griffin and Sheikh, 1999; Krajewski et al., 2000; Auer‐Grumbach et al., 2003). Extensive studies over the years have identified candidate genes and other risk factors and have provided a better understanding of neuropathies with underlying mechanisms. Interestingly, several studies have shown that antibody‐mediated immune attack against axolemma can be involved in the pathogenesis of inflammatory demyelinating neuropathies (Armati and Mathey, 2014). Surprisingly, examination of patients' sera reactivity revealed its high binding activity to the nodal and paranodal regions of myelinated axons, and the presence of autoantibodies recognizing extracellular domains of nodal proteins Neurofascin 186 and Gliomedin, as well as paranodal Caspr1, Contactin, and the glial 155‐kDa Neurofascin (Nfasc 155) (Devaux et al., 2012; Ng et al., 2012; Doppler et al., 2016). These findings suggest that axonal domains could potentially become a primary target in the pathogenesis of peripheral neuropathies, and the term nodo‐paranodopathy has been used recently to characterize autoimmune neuropathies that target these regions in myelinated fibers (Uncini et al., 2013). However, little is known about the downstream effects and mechanisms of how disrupted axonal domains can lead to neuromuscular system pathologies.
Increasing evidence from animal studies also suggests that compromised axonal domain integrity can lead to PNS myelinated fiber dysfunction and muscle pathology. For example, in the model of experimental autoimmune neuropathy, immunization of rats with peripheral myelin was accompanied by severe motor dysfunction at the peak of disease progression and led to disruption of voltage‐gated sodium channel clusters at the nodes of Ranvier in sciatic nerves (SNs), with subsequent detection of Nfasc 186 and gliomedin‐associated autoantibodies (Lonigro and Devaux, 2009). Additionally, numerous studies have proved that ablation of key nodal or paranodal proteins dramatically alters conductive properties of myelinated axons (Bhat et al., 2001; Pillai et al., 2009; Thaxton et al., 2011; Susuki et al., 2013), which potentially can modify synaptic transmission at the neuromuscular junction (NMJ) level and disrupt the cross‐talk between motor neurons and the muscles they innervate. However, knowledge of changes at the NMJ after disruption of specific axonal domains is limited to very few studies, and, to date, no further detailed investigations of possible muscle pathology have been carried out. For instance, loss of paranodal Nfasc 155, but not Caspr1, was found to alter peripheral postnatal synaptic remodeling and result in delayed synapse elimination at the NMJ (Roche et al., 2014). Moreover, ablation of protein 4.1B, which is highly enriched at the paranodal, juxtaparanodal, and internodal areas, revealed axonal swellings close to synaptic terminals of NMJs in knockout animals (Cifuentes‐Diaz et al., 2011).
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