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

Zhu, Hong, Guariglia, Sara, Yu, Raymond Y.L., Li, Wenjing, Brancho, Deborah, Peinado, Hector, Lyden, David, Salzer, James, Bennett, Craig, and Chow, Chi-Wing (2013) Mutation of SIMPLE in Charcot-Marie-Tooth 1C alters production of exosomes. Molecular Biology of the Cell, 24 (11). pp. 1619-1637.

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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. © 2013 Zhu et al.

Item ID: 35698
Item Type: Article (Research - C1)
ISSN: 1939-4586
Keywords: membrane protein; small integral membrane protein of the lysosome late endosome; unclassified drug, animal cell; animal experiment; animal model; article; B lymphocyte; cell communication; controlled study; exosome; fibroblast; gene mutation; hereditary motor sensory neuropathy; molecular pathology; mouse; multivesicular body; nonhuman; point mutation; priority journal; protein expression; protein localization; protein secretion; Schwann cell, Alleles; Amino Acid Motifs; Animals; B-Lymphocytes; Base Sequence; Biological Transport; Cell Communication; Charcot-Marie-Tooth Disease; Disease Models, Animal; Embryo, Mammalian; Exosomes; Fibroblasts; Gene Expression; Humans; Mice; Molecular Sequence Data; Multivesicular Bodies; Nervous System; Nuclear Proteins; Point Mutation; Schwann Cells; Transcription Factors
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© 2013 Zhu et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (

Funders: Muscular Dystrophy Association, USA
Date Deposited: 30 Oct 2014 04:00
FoR Codes: 06 BIOLOGICAL SCIENCES > 0604 Genetics > 060410 Neurogenetics @ 50%
11 MEDICAL AND HEALTH SCIENCES > 1109 Neurosciences > 110999 Neurosciences not elsewhere classified @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920110 Inherited Diseases (incl. Gene Therapy) @ 100%
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