Aberrant glycosylation/phosphorylation in chromatolytic motoneurons of Werdnig-Hoffmann disease

Chromatolytic motor neurons (cMN) in Werdnig-Hoffmann disease (WHD) were investigated in both spinal anterior horns and hypoglossal nuclei with both immuno- and lectin-histochemistry in six cases (3-9 months; two female and four male) of clinically typical WHD. Most characteristic findings from lectin-histochemistry were central accumulation of N-linked glycopeptides and marked general paucity of O-linked glycopeptides in cMN. Phosphorylated intermediate filaments, developmentally regulated cytoskeletons and cell adhesion molecules were abundant at the periphery of cMN, as visualized with immunohistochemistry. Both N-linked and O-linked glycoproteins were reciprocally absent or scarce at the peripheral zone of cMN. This intriguing phenomenon provided the basis for postulating the pathogenesis of WHD. The reciprocal ('yen-yang') dissociation of phosphorylation and glycosylation of neurofilament proteins was only seen with phosphorylated neurofilaments and seen only in cMN, not in the control or surrounding unaffected motoneurons. The central accumulation of N-linked glycopeptides was in contrast with peripheral absence of O-GlcNAc-linked glycopeptides which would normally be expected to colocalize with phosphorylated neurofilaments. Both O-glycosylation and phosphorylation are considered essential for assembly and network of neurofilaments. Aberrant O-glycosylation and dissociation of O-glycosylation/phosphorylation would not only cause a defect in neurofilament assembly but also neuron-glia adhesion (via a molecule such as Ng-CAM), causing a failure of lower motoneurons to synapse homophilically with the upper motoneurons and also a failure to adhere heterophilically to glia, resulting in the histopathologic tetrad ((i) central chromatolysis, (ii) empty-cell beds, (iii) migratory motoneurons and (iv) glial bundles of spinal roots) typical of WHD.