Mutation of SIMPLE in Charcot-Marie-Tooth 1C alters production of exosomes

Hong Zhu, Sara Guariglia, Raymond Y.L. Yu, Wenjing Li, Deborah Brancho, Hector Peinado, David Lyden, James Salzer, Craig Bennett, Chi Wing Chow

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Charcot-Marie-Tooth (CMT) disease is an inherited neurological disorder. Mutations in the small integral membrane protein of the lysosome/late endosome (SIMPLE) account for the rare autosomal-dominant demyelination in CMT1C patients. Understanding the molecular basis of CMT1C pathogenesis is impeded, in part, by perplexity about the role of SIMPLE, which is expressed in multiple cell types. Here we show that SIMPLE resides within the intraluminal vesicles of multivesicular bodies (MVBs) and inside exosomes, which are nanovesicles secreted extracellularly. Targeting of SIMPLE to exosomes is modulated by positive and negative regulatory motifs. We also find that expression of SIMPLE increases the number of exosomes and secretion of exosome proteins. We engineer a point mutation on the SIMPLE allele and generate a physiological mouse model that expresses CMT1C-mutated SIMPLE at the endogenous level. We find that CMT1C mouse primary embryonic fibroblasts show decreased number of exosomes and reduced secretion of exosome proteins, in part due to improper formation of MVBs. CMT1C patient B cells and CMT1C mouse primary Schwann cells show similar defects. Together the data indicate that SIMPLE regulates the production of exosomes by 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 system and account for CMT1C molecular pathogenesis.

Original languageEnglish (US)
Pages (from-to)1619-1637
Number of pages19
JournalMolecular biology of the cell
Volume24
Issue number11
DOIs
StatePublished - Jun 1 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Zhu, H., Guariglia, S., Yu, R. Y. L., Li, W., Brancho, D., Peinado, H., Lyden, D., Salzer, J., Bennett, C., & Chow, C. W. (2013). Mutation of SIMPLE in Charcot-Marie-Tooth 1C alters production of exosomes. Molecular biology of the cell, 24(11), 1619-1637. https://doi.org/10.1091/mbc.E12-07-0544