Identifying the genetic basis of a disease is only a small step toward understanding its pathogenesis, as Simons et al. clearly demonstrate on page 327. The dysmyelinating condition Pelizaeus-Merzbacher disease (PMD) is caused by duplication oroverexpression of the myelin proteolipid protein (PLP) gene, but it was not clear if excess PLP caused dysmyelination directly or indirectly. Simons et al. characterized the changes in intracellular trafficking caused by PLP overexpression in three systems. Their findings help define a pathway that may transport myelin rafts in oligodendrocytes, and suggest that PLP overexpression causes PMD by a multistep, indirect mechanism.
Figure .
PLP (green) gets misrouted to late endosomes (red).
The authors examined BHK cells, oligodendrocytes, and transgenic mice in which PLP was overexpressed. In these systems, PLP is not incorporated into lipid rafts, but is routed to late endosomes/lysosomes. Cholesterol then accumulates in these compartments, which normally maintain low cholesterol levels. Two fluorescently labeled sphingolipid analogues and GPI-YFP are also missorted to late endosomes/lysosomes in PLP-overexpressing cells.
Based on these and earlier results, the authors propose that PLP overexpression saturates the myelin raft transport pathway, causing the surplus PLP to be routed to the degradative compartment. This rerouting also causes the misdirection of cholesterol, and eventually other raft components, to the late endosome/lysosome.
Thus PLP overexpression may trigger a chain of events that could trap myelin lipids, impair normal trafficking of late endosomes/lysosomes, and interfere with myelination- regulating signaling molecules that localize to lipid rafts. These defects may trigger the premature oligodendrocyte death seen in mouse models of PMD. The authors are now trying to identify the mechanism by which cell death is induced in PLP-overexpressing cells. ▪