Hereditary sensory neuropathy type 1-associated deoxysphingolipids cause neurotoxicity, acute calcium handling abnormalities and mitochondrial dysfunction in vitro

Neurobiology of Disease
Emma R WilsonBernadett Kalmar

Abstract

Hereditary sensory neuropathy type 1 (HSN-1) is a peripheral neuropathy most frequently caused by mutations in the SPTLC1 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 d...Continue Reading

Citations

Sep 12, 2019·The New England Journal of Medicine·Marin L GantnerMartin Friedlander
Nov 20, 2019·Neurology. Genetics·Federica BosoGian Maria Fabrizi
Feb 15, 2020·Journal of Neurochemistry·Katrin A BeckerStefka D Spassieva
Jul 10, 2019·International Journal of Molecular Sciences·Rossella Indellicato, Marco Trinchera
Aug 10, 2020·Journal of Neurology, Neurosurgery, and Psychiatry·Mary M Reilly, Alexander M Rossor
Dec 29, 2020·Cellular Signalling·Brenda Wan Shing LamDeron R Herr
Aug 25, 2019·Progress in Lipid Research·A C CarreiraL C Silva
Feb 7, 2021·Neuromolecular Medicine·Emma J ArsenaultBrian M Barth
Aug 31, 2021·JAMA Neurology·Janel O JohnsonElisabetta Zucchi

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