Consequences of a traffic jam

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.

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...