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

Abstract

Bidirectional interactions between neurons and myelinating glial cells result in formation of axonal domains along myelinated fibers. Loss of axonal domains leads to detrimental consequences on nerve structure and function resulting in reduced conductive properties and the diminished ability to reliably transmit signals to the targets they innervate. Thus, impairment of peripheral myelinated axons that project to the surface of muscle fibers and form neuromuscular junction (NMJ) synapses leads to muscle dysfunction. The goal of our studies was to determine how altered electrophysiological properties due to axonal domains disorganization lead to muscle pathology, which is relevant to a variety of peripheral neuropathies, demyelinating diseases and neurodegenerative disorders. Using conventional Contactin-Associated Protein 1 (Caspr1) and Caspr2 single or double mutants with disrupted paranodal, juxtaparanodal or both regions, respectively, in peripheral myelinated axons, we correlated defects in NMJ integrity and muscle pathology. Our data show that loss of axonal domains in Caspr1 and Caspr2 single and double mutants primarily alters distal myelinated fibers together with presynaptic terminals, eventually leading to NMJ denervation and reduction in postsynaptic endplate areas. Moreover, reduction in conductive properties of peripheral myelinated fibers together with NMJ disintegration leads to muscle atrophy in Caspr1 mutants or muscle fiber degeneration accompanied with mitochondrial dysfunction in Caspr1/Caspr2 double mutants. Together our data indicate that proper organization of axonal domains in myelinated fibers is critical for optimal propagation of electrical signals, NMJ integrity and muscle health, and provide insights into a wide range of pathologies that result in reduced nerve conduction leading to muscle atrophy.

mTORC1 Activation by Loss of Tsc1 in Myelinating Glia Causes Downregulation of Quaking and Neurofascin 155 Leading to Paranodal Domain Disorganization

“…The paranodes serve as a membrane barrier that protects nodes and excludes juxtaparanodal components from invading into the nodal areas (Thaxton et al, 2011 ). The localization of Caspr at the paranodes depends on the presence of Nfasc NF155 proteins (Pillai et al, 2009 ), thus downregulation of Nfasc NF155 affects paranodal organization leading to changes in nerve conduction properties, as is observed in other mutants (Saifetiarova et al, 2017a , b ), similar to Tsc1 cKO mutant described here. Together our findings further underscore that mTORC1 activation has more global consequences on myelination and myelinated axon structure, which underlies deficits in nerve conduction properties and neurological phenotypes in Tsc1 mutants.…”

Assembly and Function of the Juxtaparanodal Kv1 Complex in Health and Disease

“…More precisely, in the Contactin2 KO mice, Kv1.2 is missing in 70% of the juxtaparanodes of the sciatic nerves and the Kv1.2 immunoreactivity occupies much-reduced areas abutting the paranodes in the optic nerves [ 41 ]. The phenotype seems to be quite similar in Caspr2-deficient mice with the loss of Kv1 immunoreactivity in most of the juxtaparanodes of the sciatic and optic nerves as reported by Poliak et al (2003) [ 42 ] or a severe reduction of Kv1 concentration in most of the juxtaparanodes in the spinal cord and sciatic nerve depending on the age examined between P20 and P180 [ 66 ]. In myelinated peripheral axons, the Kv1 channels associated with Caspr2 and Contactin2 are also found along the two lines flanking the mesaxonal line affixed to the inner lip of the myelin sheath along the internodes and below the Schmidt–Lanterman incisures where they may attenuate current leakage [ 67 ].…”

Ablation of cytoskeletal scaffolding proteins, Band 4.1B and Whirlin, leads to cerebellar purkinje axon pathology and motor dysfunction

“…Formation of swellings along myelinated fibers is a hallmark of altered axonal transport, which is highly dependent on intact cytoskeleton. Disrupted cytoskeleton, accompanied with misoriented microtubules and neurofilaments, leads to changes in cellular organelles and protein transport, and their aggregated accumulation along the axons (Garcia-Fresco et al, 2006; Pillai et al, 2007; Saifetiarova et al, 2017a). Interestingly, we found a greater number of axonal swellings were formed in dKO animals, compared to single 4.1B KO and WKO mice, suggesting more severely affected axonal transport in those animals (Fig.…”