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A Model of Hereditary Sensory and Autonomic Neuropathy Type 1 Reveals a Role of Glycosphingolipids in Neuronal Polarity
Mengqiao Cui1; Rong Ying1; Xue Jiang1; Gang Li1; Xuanjun Zhang1; Jun Zheng1; Kin Yip Tam1; Bin Liang2; Anbing Shi3; Verena Göbel4; Hongjie Zhang1,5
2019-07-17
Source PublicationJOURNAL OF NEUROSCIENCE
ISSN0270-6474
Volume39Issue:29Pages:5816-5834
Abstract

Hereditary sensory and autonomic neuropathy Type 1 (HSAN1) is a rare autosomal dominantly inherited neuropathy, clinically characterized by a loss of distal peripheral sensory and motoneuronal function. Mutations in subunits of serine palmitoyltransferase (SPT) have been linked to the majority of HSAN1 cases. SPTs catalyze the condensation of l-serine with palmitoyl-CoA, the first committed and rate-limiting step in de novo sphingolipid biosynthesis. Despite extensive investigation, the molecular pathogenesis of HSAN1 remains controversial. Here, we established a Caenorhabditis elegans (C. elegans) model of HSAN1 by generating a sptl-1(c363g) mutation, encoding SPTL-1(C121W) and equivalent to human SPTLC1C133W, at the C. elegans genomic locus through CRISPR. The sptl-1(c363g) homozygous mutants exhibited the same larval lethality and epithelial polarity defect as observed in sptl-1(RNAi) animals, suggesting a loss-of-function effect of the SPTL-1(C121W) mutation. sptl-1(c363g)/+ heterozygous mutants displayed sensory dysfunction with concomitant neuronal morphology and axon-dendrite polarity defects, demonstrating that the C. elegans model recapitulates characteristics of the human disease. sptl-1(c363g)-derived neuronal defects were copied in animals with defective sphingolipid biosynthetic enzymes downstream of SPTL-1, including ceramide glucosyltransferases, suggesting that SPTLC1C133W contributes to the HSAN1 pathogenesis by limiting the production of complex sphingolipids, including glucosylceramide. Overexpression of SPTL-1(C121W) led to similar epithelial and neuronal defects and to reduced levels of complex sphingolipids, specifically glucosylceramide, consistent with a dominant-negative effect of SPTL-1(C121W) that is mediated by loss of this downstream product. Genetic interactions between SPTL-1(C121W) and components of directional trafficking in neurons suggest that the neuronal polarity phenotype could be caused by glycosphingolipid-dependent defects in polarized vesicular trafficking.

KeywordAxonal Transport Glucosylceramide Hsan1 Neuronal Polarity Sphingolipidomics Sphingolipids
DOI10.1523/JNEUROSCI.2541-18.2019
Indexed BySCIE
Language英语
WOS Research AreaNeurosciences & Neurology
WOS SubjectNeurosciences
WOS IDWOS:000475772200016
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Cited Times [WOS]:6   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Affiliation1.Faculty of Health Sciences, University of Macau, Taipa, Macau SAR 999078, China
2.Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
3.Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
4.Mucosal Immunology and Biology Research Center, Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
5.Center of Reproduction, Development and Ageing, University of Macau, Taipa, Macau SAR 999078, China
First Author AffilicationFaculty of Health Sciences
Recommended Citation
GB/T 7714
Mengqiao Cui,Rong Ying,Xue Jiang,et al. A Model of Hereditary Sensory and Autonomic Neuropathy Type 1 Reveals a Role of Glycosphingolipids in Neuronal Polarity[J]. JOURNAL OF NEUROSCIENCE,2019,39(29):5816-5834.
APA Mengqiao Cui.,Rong Ying.,Xue Jiang.,Gang Li.,Xuanjun Zhang.,...&Hongjie Zhang.(2019).A Model of Hereditary Sensory and Autonomic Neuropathy Type 1 Reveals a Role of Glycosphingolipids in Neuronal Polarity.JOURNAL OF NEUROSCIENCE,39(29),5816-5834.
MLA Mengqiao Cui,et al."A Model of Hereditary Sensory and Autonomic Neuropathy Type 1 Reveals a Role of Glycosphingolipids in Neuronal Polarity".JOURNAL OF NEUROSCIENCE 39.29(2019):5816-5834.
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