Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids

Anke Penno, Mary M. Reilly, Henry Houlden, Matilde Laurá, Katharina Rentsch, Vera Niederkofler, Esther T. Stoeckli, Garth Nicholson, Florian Eichler, Robert H. Brown, Arnold Von Eckardstein, Thorsten Hornemann*

*Corresponding author for this work

Research output: Contribution to journalArticle

184 Citations (Scopus)

Abstract

HSAN1 is an inherited neuropathy found to be associated with several missense mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT). SPT catalyzes the condensation of serine and palmitoyl-CoA, the initial step in the de novo synthesis of sphingolipids. Here we show that the HSAN1 mutations induce a shift in the substrate specificity of SPT, which leads to the formation of the two atypical deoxysphingoid bases (DSBs) 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine. Both metabolites lack the C1 hydroxyl group of sphinganine and can therefore neither be converted to complex sphingolipids nor degraded. Consequently, they accumulate in the cell, as demonstrated in HEK293 cells over-expressing mutant SPTLC1 and lymphoblasts of HSAN1 patients. Elevated DSB levels were also found in the plasma of HSAN1 patients and confirmed in three groups of HSAN1 patients with different SPTLC1mutations. The DSBs show pronounced neurotoxic effects on neurite formation in cultured sensory neurons. The neurotoxicity co-occurs with a disturbed neurofilament structure in neurites when cultured in the presence of DSBs. Based on these observations, we conclude that HSAN1 is caused by a gain of function mutation, which results in the formation of two atypical and neurotoxic sphingolipid metabolites.

Original languageEnglish
Pages (from-to)11178-11187
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number15
DOIs
Publication statusPublished - 9 Apr 2010
Externally publishedYes

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    Penno, A., Reilly, M. M., Houlden, H., Laurá, M., Rentsch, K., Niederkofler, V., ... Hornemann, T. (2010). Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids. Journal of Biological Chemistry, 285(15), 11178-11187. https://doi.org/10.1074/jbc.M109.092973