Evaluating epigenetic landmarks in the brain of multiple sclerosis patients: a contribution to the current debate on disease pathogenesis

Abstract

The evidence suggesting a role of epigenetics in the definition of complex trait diseases is rapidly increasing. The gender prevalence of multiple sclerosis, the low level concordance in homozygous twins and the linkage to several genetic loci, suggest an epigenetic component to the definition of this demyelinating disorder. While the immune etio-pathogenetic mechanism of disease progression has been well characterized, still relatively little is known about the initial events contributing to onset and progression of the demyelinating lesion. This article addresses the challenging question of whether loss of the mechanisms of epigenetic regulation of gene expression in the myelinating cells may contribute to the pathogenesis of multiple sclerosis, by affecting the repair process and by modulating the levels of enzymes involved in neo-epitope formation. The role of altered post-translational modifications of nucleosomal histones and DNA methylation in white matter oligodendroglial cells are presented in terms of pathogenetic concepts and the relevance to therapeutic intervention is then discussed.

Fig. 1

Schematic drawing of the current hypotheses for MS etiologyaetiology. In black is a simplified drawing of the current pathogenetic hypothesis. In red is the hypothesis that is proposed in this review.

Fig. 2

Aberrant recapitulation of developmental epigenetic landmarks in multiple sclerosis. This drawing illustrates the major epigenetic events occurring in differentiating oligodendroglial cells during development (green) and leading to repression of the differentiation inhibitors Hes5 and stathmin. In the brain of multiple sclerosis patients, in contrast, these repressive epigenetic events are replaced by activating events (red arrow) leading to re-expression of differentiation inhibitors (Hes5) and of molecules destabilizing the cytoskeletal network of oligodendroglial cells (stathmin).

Fig. 3

A Proposed epigenetic mechanism of PAD2 up-regulation in MS oligodendrocytes. The upstream regulatory region of the PAD2 gene contains a CpG island. In normal individuals the methylation and expression of PAD2 is under homeostatic regulation. However in MS white matter the cytosines in CG dinucleotides in the PAD2 promoter become demethylated via increased DNA demethylase activity. The result of this CpG demethylation might explain why there is hypercitrullination of arginine rich protein substrates like myelin basic protein. Myelin basic protein once citrullinated in the normal appearing white matter loses its interactions with myelin membranes, which fragment thereby leading to autoimmune progression and MS.