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Serine palmitoyltransferase in hereditary sensory neuropathy type I


Penno, A K. Serine palmitoyltransferase in hereditary sensory neuropathy type I. 2010, ETH Zurich, Dep. für Biologie.

Abstract

Hereditary sensory neuropathy type I (HSN1) is a dominantly inherited progressive and length dependent axonal peripheral neuropathy usually starting in early adulthood. The disease was associated with several point mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT). SPT
catalyzes the condensation of L-serine and palmitoyl-CoA to sphinganine, the initial step in the de novo synthesis of sphingolipids. Here we demonstrate that HSN1 mutations induce a shift in the substrate specificity of SPT, from its preferred substrate L-serine towards the use of L-alanine and glycine. This leads to the formation of the two atypical 1-deoxy-sphingoid bases (DSBs). These
metabolites lack the C1 hydroxyl group of sphinganine, and can therefore neither be converted to complex sphingolipids nor degraded by the classical pathway. Consequently, they accumulate in cells which express the mutant form of SPT. This is demonstrated in mutant overexpressing HEK293 cells
and lymphoblast cell lines of HSN1 patients. Elevated DSB levels were also found in the plasma of HSN1 patients with different SPTLC1 mutations. DSBs are cytotoxic and induce pronounced pathological effects on neurite and cytoskeleton stability of cultured sensory neurons. Furthermore,
mice which are transgenic for HSN1 mutant SPT develop hyperalgesia at 12 months of age and hypoalgesia at 14 months of age. The mice show significantly elevated DSB levels in plasma and peripheral nerve but not in the central nervous system. Double transgenic mice which co-overexpress the wild type and mutant SPT are protected and show significant lower DSB levels. Based on these
findings, we propose that HSN1 is caused by the formation of neurotoxic sphingolipids.
Kinetic analyses of HSN1 mutants compared to wild type SPT indicate no change in the substrate affinity for L-serine but a decreased enzymatic activity for L-serine, a slightly increased affinity for Lalanine and mutation-dependent changes in the catalytic activity for L-alanine. In addition, SPT shows positive substrate cooperativity for L-serine and negative substrate cooperativity for L-alanine.
The formation of DSBs is therefore efficiently suppressed by increased L-serine concentrations. We tested L-serine supplementation as a potential therapy approach in the HSN1 transgenic mice, receiving either an L-serine or L-alanine enriched diet. L-serine supplemented mice showed a great
reduction in plasma DSB levels. They remained healthy and did not develop signs of neuronal degeneration up to the age of 20 months (end of the study). In contrast, L-alanine supplemented mice developed severe neurological deficits after already 3 months of feeding (6 months of age). The
efficacy of L-serine supplementation was further confirmed in a pilot trial in which 14 HSN1 patients received for a period of 10 weeks either an oral supplementation of 200 mg L-serine/kg bodyweight/day or 400 mg L-serine/kg bodyweight/day. Upon L-serine supplementation, plasma
DSB levels dropped significantly and reached normal levels after six weeks in both groups. In conclusion, HSN1 could become treatable by a life-long L-serine supplementation therapy.

Abstract

Hereditary sensory neuropathy type I (HSN1) is a dominantly inherited progressive and length dependent axonal peripheral neuropathy usually starting in early adulthood. The disease was associated with several point mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT). SPT
catalyzes the condensation of L-serine and palmitoyl-CoA to sphinganine, the initial step in the de novo synthesis of sphingolipids. Here we demonstrate that HSN1 mutations induce a shift in the substrate specificity of SPT, from its preferred substrate L-serine towards the use of L-alanine and glycine. This leads to the formation of the two atypical 1-deoxy-sphingoid bases (DSBs). These
metabolites lack the C1 hydroxyl group of sphinganine, and can therefore neither be converted to complex sphingolipids nor degraded by the classical pathway. Consequently, they accumulate in cells which express the mutant form of SPT. This is demonstrated in mutant overexpressing HEK293 cells
and lymphoblast cell lines of HSN1 patients. Elevated DSB levels were also found in the plasma of HSN1 patients with different SPTLC1 mutations. DSBs are cytotoxic and induce pronounced pathological effects on neurite and cytoskeleton stability of cultured sensory neurons. Furthermore,
mice which are transgenic for HSN1 mutant SPT develop hyperalgesia at 12 months of age and hypoalgesia at 14 months of age. The mice show significantly elevated DSB levels in plasma and peripheral nerve but not in the central nervous system. Double transgenic mice which co-overexpress the wild type and mutant SPT are protected and show significant lower DSB levels. Based on these
findings, we propose that HSN1 is caused by the formation of neurotoxic sphingolipids.
Kinetic analyses of HSN1 mutants compared to wild type SPT indicate no change in the substrate affinity for L-serine but a decreased enzymatic activity for L-serine, a slightly increased affinity for Lalanine and mutation-dependent changes in the catalytic activity for L-alanine. In addition, SPT shows positive substrate cooperativity for L-serine and negative substrate cooperativity for L-alanine.
The formation of DSBs is therefore efficiently suppressed by increased L-serine concentrations. We tested L-serine supplementation as a potential therapy approach in the HSN1 transgenic mice, receiving either an L-serine or L-alanine enriched diet. L-serine supplemented mice showed a great
reduction in plasma DSB levels. They remained healthy and did not develop signs of neuronal degeneration up to the age of 20 months (end of the study). In contrast, L-alanine supplemented mice developed severe neurological deficits after already 3 months of feeding (6 months of age). The
efficacy of L-serine supplementation was further confirmed in a pilot trial in which 14 HSN1 patients received for a period of 10 weeks either an oral supplementation of 200 mg L-serine/kg bodyweight/day or 400 mg L-serine/kg bodyweight/day. Upon L-serine supplementation, plasma
DSB levels dropped significantly and reached normal levels after six weeks in both groups. In conclusion, HSN1 could become treatable by a life-long L-serine supplementation therapy.

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Additional indexing

Item Type:Dissertation
Referees:Suter U, von Eckardstein A, Sauer U, Hornemann T
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Clinical Chemistry
Dewey Decimal Classification:610 Medicine & health
540 Chemistry
Date:2010
Deposited On:17 Feb 2011 10:02
Last Modified:12 Aug 2017 08:45
Additional Information:Submitted to ETH Zurich
Publisher DOI:https://doi.org/10.3929/ethz-a-006199690
Other Identification Number:Diss., Eidgenössische Technische Hochschule ETH Zürich, Nr. 19209, 2010

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