TY - JOUR
T1 - Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids
AU - Penno, Anke
AU - Reilly, Mary M.
AU - Houlden, Henry
AU - Laurá, Matilde
AU - Rentsch, Katharina
AU - Niederkofler, Vera
AU - Stoeckli, Esther T.
AU - Nicholson, Garth
AU - Eichler, Florian
AU - Brown, Robert H.
AU - Von Eckardstein, Arnold
AU - Hornemann, Thorsten
PY - 2010/4/9
Y1 - 2010/4/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77951218516&partnerID=8YFLogxK
U2 - 10.1074/jbc.M109.092973
DO - 10.1074/jbc.M109.092973
M3 - Article
C2 - 20097765
AN - SCOPUS:77951218516
SN - 0021-9258
VL - 285
SP - 11178
EP - 11187
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 15
ER -