Molecular pathology of Multiple Sclerosis lesions reveals a heterogeneous expression pattern of genes involved in oligodendrogliogenesis.

Little is known about the decisive molecular factors that regulate lesion remyelination in Multiple Sclerosis. To identify such factors, we performed a differential gene expression analysis of normal appearing white matter (NAWM), active, remyelinating, and inactive demyelinated lesions. As expected, many genes involved in inflammatory processes were detected to be differentially regulated between these tissue types. Among them, we found an increased expression of members of the STAT6 pathway such as STAT6, IL4 and IL4R in active, remyelinated and inactive demyelinated lesions. This suggests that a protective, anti-inflammatory reaction, as already reported to be present in MS NAWM, is further enhanced in lesion tissues. Focusing on genes influencing oligodendrogliogenesis, we found a decreased expression of NKX2-2 in active, remyelinated and inactive demyelinated lesions, whereas SOX10 was downregulated in inactive demyelinated lesions, when compared to NAWM. Simultaneously, CXCL12 (SDF1) expression was strongly increased in active, remyelinated and inactive demyelinated lesions, but increased expression of the IGF1 and IGF2 genes was found in inactive demyelinated lesions. This demonstrates that, in principle, expression of genes promoting oligodendrogliogenesis occurs in MS lesion tissue - even in inactive demyelinated lesions. In contrast, oligodendrogenesis inhibiting genes such as JAG1 were also expressed at higher levels in inactive demyelinated lesions. Both, oligodendrogliogenesis promoting as well as inhibiting genes are expressed in all lesion tissues. However, no clear promoting or inhibiting expression pattern could be detected in any of the different types of lesioned tissues. This might reflect the heterogeneity of lesion development in MS patients, both in terms of mechanisms and temporal differences.

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

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.