Mutation of SIMPLE in Charcot‐Marie‐Tooth 1C Alters Production of Exosomes

Abstract

Charcot‐Marie‐Tooth (CMT) disease is an inherited neurological disorder. Mutations in protein SIMPLE accounts for the rare autosomal dominant demyelination in type 1C CMT patients (CMT1C). Understanding the molecular basis of CMT1C pathogenesis is impeded, in part, by the perplexity for the role of SIMPLE, an evolutionarily conserved protein expressed in multiple cell types. Here, we show that SIMPLE plays a role in the production of exosomes, which are nanovesicles secreted extracellularly. We find that SIMPLE resides within the intraluminal vesicles of multivesicular bodies and inside exosomes. Expression of SIMPLE increases the production of exosomes. Conversely, endogenous SIMPLE carrying CMT1C mutation in primary mouse embryonic fibroblasts shows reduced secretion of exosomes, in part, due to improper formation of MVBs. CMT1C patient B cells also show similar defects in exosomes and MVBs. Together, these data indicate that SIMPLE regulates the production of exosomes via modulating the formation of MVBs. Dysregulated endosomal trafficking and changes in the landscape of exosome‐mediated intercellular communications may place an overwhelming burden on the nervous systems and, account for the CMT1C molecular pathogenesis.