A SIMPLE explanation for Charcot-Marie-Tooth disease

Lee et al. reveal how a protein linked to the peripheral neuropathy Charcot-Marie-Tooth disease (CMT) regulates the endosomal trafficking and activity of signaling receptors.

CMT type 1C is an autosomal dominant form of the disease caused by mutations in an early endosomal protein called SIMPLE. SIMPLE’s function is unknown, though the protein interacts with Tsg101, a component of the endosomal ESCRT-I complex that sorts proteins for delivery to late endosomes and lysosomes. Lee et al. found that SIMPLE also associated with STAM1 and Hrs, which together form the ESCRT-0 complex that promotes the initial step of endosomal sorting.

All three of these ESCRT proteins were recruited less efficiently to endosomes in the absence of SIMPLE, thereby inhibiting endosome-to-lysosome transport. EGF usually induces the degradation of its receptor, ErbB1, by stimulating the receptor’s internalization and delivery to lysosomes. But ErbB1 was trapped in the early endosomes of HeLa cells lacking SIMPLE, prolonging the receptor’s signaling activity to downstream MAP kinases. CMT-linked SIMPLE mutants were unable to restore ErbB1 trafficking and even acted as dominant negatives to impair ESCRT localization and endosomal sorting in the presence of wild-type SIMPLE.

Schwann cells, which normally form the myelin sheath around peripheral nerves, are progressively lost in CMT type 1C patients. Lee et al. found that degradation and inactivation of the neuregulin receptors ErbB2 and ErbB3 were delayed in Schwann cells expressing SIMPLE mutants. Lee et al. now want to generate transgenic mice to test whether prolonged activity of this signaling pathway causes the demyelination associated with CMT type 1C.