Early reduction of myelin-associated glycoprotein at myelin membranes in Huntington's disease.

Huntington's disease (HD) is marked by progressive neuronal loss and atrophy of grey matter structures, particularly the caudate and putamen. Brain imaging studies reveal that the white matter starts to decay in the brain of individuals bearing the HD mutation many years before symptomatic onset. However, the mechanism by which the HD mutation causes white matter loss remains to be further defined. In this study, we examined white matter pathology and explored the underlying mechanism in the HDQ140 knock-in mouse model of HD. Western blot analysis of proteins localized at different layers of the myelin sheath showed that myelin-associated glycoprotein (MAG), which is localized at the innermost myelin layer, was decreased earlier than proteins localized at outer layers of the myelin. The loss of MAG occurred at fully myelinated axons and was progressive with age. In postmortem symptomatic human HD brains, the level of MAG as well as other myelin proteins was also decreased. In HD mouse brains, MAG labeling was reduced at fiber bundles but accumulated in perinuclear structures of cells that expressed breast carcinoma amplified sequence 1, a marker for new oligodendrocytes. While their abundance was normal, new oligodendrocytes in HD brains were impeded in acquiring the expression of MAG. Compared with those in wild-type mouse brains, oligodendrocytes in HD mouse brains had a reduced frequency of MAG-bearing small vesicles and an increased abundance and enlargement of MAG-containing perinuclear structures. Further studies suggest that the MAG-accumulating perinuclear structures were derived from the late endosomal lysosomal compartment. Our study suggests that white matter decay in HD brains involves an early progressive loss of MAG in myelin membranes.