A model of hereditary sensory and autonomic neuropathy type 1 reveals a role of glycosphingolipids in neuronal polarity

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	A model of hereditary sensory and autonomic neuropathy type 1 reveals a role of glycosphingolipids in neuronal polarity
	Cui, M.; Ying, R.; Jiang, X.; Gobel, V.; Zhang, H.
	2019-06-01
Source Publication	22nd International C. elegans Conference Abstract Book
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 are the enzymes that 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 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 defects 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, for instance glucosylceramides. Overexpression of SPTL-1(C121W) led to similar epithelial and neuronal defects as well as to reduced levels of complex sphingolipids, specifically glucosphingolipids, consistent with a dominant-negative effect of SPTL-1(C121W). Genetic interactions between SPTL-1(C121W) and the clathrin adaptor AP3 and kinesin could suggest that the neuronal polarity phenotype is caused by defects in polarized vesicular trafficking, e.g. via loss of glycosphingolipids.
Keyword	HSAN1 glycosphingolipids neuronal polarity
Language	英語English
The Source to Article	PB_Publication
PUB ID	46783
Document Type	Conference paper
Collection	DEPARTMENT OF BIOMEDICAL SCIENCES Faculty of Health Sciences
Corresponding Author	Zhang, H.
Recommended Citation GB/T 7714	Cui, M.,Ying, R.,Jiang, X.,et al. A model of hereditary sensory and autonomic neuropathy type 1 reveals a role of glycosphingolipids in neuronal polarity[C], 2019.
APA	Cui, M.., Ying, R.., Jiang, X.., Gobel, V.., & Zhang, H. (2019). A model of hereditary sensory and autonomic neuropathy type 1 reveals a role of glycosphingolipids in neuronal polarity. 22nd International C. elegans Conference Abstract Book.

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