title: 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 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.
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York, NY 10461, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Sara
authors.initials: S
authors.lastname: Guariglia
authors.forename: Raymond Y L
authors.initials: RY
authors.lastname: Yu
authors.forename: Wenjing
authors.initials: W
authors.lastname: Li
authors.forename: Deborah
authors.initials: D
authors.lastname: Brancho
authors.forename: Hector
authors.initials: H
authors.lastname: Peinado
authors.forename: David
authors.initials: D
authors.lastname: Lyden
authors.forename: James
authors.initials: J
authors.lastname: Salzer
authors.forename: Craig
authors.initials: C
authors.lastname: Bennett
authors.forename: Chi-Wing
authors.initials: CW
authors.lastname: Chow
mesh_terms: D000483:Alleles; D020816:Amino Acid Motifs; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D001692:Biological Transport; D002450:Cell Communication; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D055354:Exosomes / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D057146:Multivesicular Bodies / Q000378:metabolism / Q000473:pathology; D009420:Nervous System / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D012583:Schwann Cells / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C118738:LITAF protein, human; C492727:Litaf protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors