期刊
NEUROBIOLOGY OF DISEASE
卷 117, 期 -, 页码 1-14出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2018.05.008
关键词
Sphingolipid; Deoxysphingolipid; Neuron; Peripheral neuropathy; ES-285; Mitochondria; Endoplasmic reticulum
资金
- Medical Research Council (MRC) Centre for Neuromuscular Diseases, MRC Centre Grant [G0601943]
- Brain Research Trust
- National Institutes of Neurological Diseases and Stroke and Office of Rare Diseases [U54NS065712]
- UCLH Charities
- European Community's Seventh Framework Programme (FP7) [259867]
- Department of Health's National Institute for Health Research Biomedical Research Centres [BRC51/NS/MR]
- Medical Research Council [1354730] Funding Source: researchfish
- MRC [MR/M003418/1] Funding Source: UKRI
Hereditary sensory neuropathy type 1 (HSN-1) is a peripheral neuropathy most frequently caused by mutations in the SPTLCI or SPTLC2 genes, which code for two subunits of the enzyme serine palmitoyltransferase (SPT). SPT catalyzes the first step of de novo sphingolipid synthesis. Mutations in SPT result in a change in enzyme substrate specificity, which causes the production of atypical deoxysphinganine and deoxymethylsphinganine, rather than the normal enzyme product, sphinganine. Levels of these abnormal compounds are elevated in blood of HSN-1 patients and this is thought to cause the peripheral motor and sensory nerve damage that is characteristic of the disease, by a largely unresolved mechanism. In this study, we show that exogenous application of these deoxysphingoid bases causes dose- and time-dependent neurotoxicity in primary mammalian neurons, as determined by analysis of cell survival and neurite length. Acutely, deoxysphingoid base neurotoxicity manifests in abnormal Ca2+ handling by the endoplasmic reticulum (ER) and mitochondria as well as dysregulation of cell membrane store-operated Ca2+ channels. The changes in intracellular Ca2+ handling are accompanied by an early loss of mitochondrial membrane potential in deoxysphingoid base-treated motor and sensory neurons. Thus, these results suggest that exogenous deoxysphingoid base application causes neuronal mitochondrial dysfunction and Ca2+ handling deficits, which may play a critical role in the pathogenesis of HSN-1.
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