Disruption of neurofascin localization reveals early changes preceding demyelination and remyelination in multiple sclerosis

Abstract

Saltatory conduction in the nervous system is enabled through the intimate association between the leading edge of the myelin sheath and the axonal membrane to demarcate the node of Ranvier. The 186 kDa neuron specific isoform of the adhesion molecule neurofascin (Nfasc186) is required for the clustering of voltage gated Na+ channels at the node, whilst the 155 kDa glial specific isoform (Nfasc155) is required for the assembly of correct paranodal junctions. In order to understand the relationship between these vital structures and how they are affected in multiple sclerosis we have examined the expression of Nfasc155 and Nfasc186 in areas of inflammation, demyelination and remyelination from post-mortem brains. Fourteen cases of neuropathologically confirmed multiple sclerosis (8 female and 6 male; post-mortem delay 7-24 h; age 37-77 years; and disease duration 15-40 years), comprising 20 tissue blocks with 32 demyelinating or remyelinating lesions, were used in this study. A significant early alteration in Nfasc155+ paranodal structures occurs within and adjacent to actively demyelinating white matter lesions that are associated with damaged axons. Shaker-type Kv1.2 channels, normally located distally to the paranode, overlapped with the disrupted Nfasc155+ structures. In the absence of Nfasc155, Kv1.2 channels abutted normally clustered Nfasc186+ nodes, indicating that complete disruption of the paranodal structure and movement of Kv1.2 channels precede alterations at the node itself. Within areas of partial remyelination, a number of atypical triple-Nfasc155+ structures were noted that may represent transient oligodendrocyte-axonal contacts during the process of myelin repair or aberrant interactions. Within shadow plaques discretely clustered Na+v, Nfasc186+ and Nfasc155+ domains indicated the restoration of normal nodal architecture. The alterations in oligodendrocyte Nfasc155 expression that accompany inflammation and demyelination suggest an ongoing disruption to the axonal-oligodendrocyte complex within newly forming as well as established lesions in multiple sclerosis, resulting in destruction of the Nfasc186+/Na+v nodal complex vital to successful fast neurotransmission in the CNS.

Paranodal Myelin Damage after Acute Stretch in Guinea Pig Spinal Cord

“…6G-I). Similar redistribution of potassium channels has been previously reported in chronic spinal cord injury (Karimi-Abdolrezaee et al, 2004;Nashmi et al, 2000) and multiple sclerosis (Howell et al, 2006). However, the defining factor of the current study is that the exposure and migration of the voltage-dependent potassium channels was observed in reference to myelin structure, which was imaged simultaneously using a label-free CARS technique.…”

Targeted Ablation of Oligodendrocytes Induces Axonal Pathology Independent of Overt Demyelination

“…Notably, mice deficient in Nfasc155 or Caspr do not form normal paranodes and exhibit aberrant clustering of voltagegated ion channels on axons resulting in various motor deficits (Bhat et al, 2001;Rios et al, 2003;Pillai et al, 2009). In MS subjects, Caspr and Nfasc155 are abnormally distributed on myelinated axons that border chronic demyelinated lesions (Wolswijk and Balesar, 2003;Howell et al, 2006) suggesting that changes in paranodal integrity could occur at the leading edge of MS lesion formation before demyelination. Paranodal eversion has also been described in transgenic mice with additional copies of the plp gene (Tanaka et al, 2009) and in CGT mutant mice that have aberrant but viable oligodendrocytes (Dupree et al, 1998).…”

Progressive Disorganization of Paranodal Junctions and Compact Myelin Due to Loss of DCC Expression by Oligodendrocytes

“…Paranodal defects have also been proposed to constitute a predisposition to neuroinflammation leading to the development of demyelinating diseases such as multiple sclerosis (MS;Mastronardi and Moscarello, 2005). The disruption of paranodal junctions has been identified as an early sign of demyelination around MS lesions (Wolswijk and Balesar, 2003;Howell et al, 2006). Notably, a recent proteomic analysis of CSF samples collected from children during their initial presentation of CNS inflammation, who were subsequently diagnosed as having MS, identified elevated levels of proteins enriched at the node of Ranvier and paranodal junction, including elevated levels of DCC, but did not detect compact myelin proteins (Dhaunchak et al, 2012).…”