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Oral l-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1
Kevin Garofalo, … , Thorsten Hornemann, Florian S. Eichler
Kevin Garofalo, … , Thorsten Hornemann, Florian S. Eichler
Published November 1, 2011
Citation Information: J Clin Invest. 2011;121(12):4735-4745. https://doi.org/10.1172/JCI57549.
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Research Article Article has an altmetric score of 7

Oral l-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1

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Abstract

Hereditary sensory and autonomic neuropathy type 1 (HSAN1) causes sensory loss that predominantly affects the lower limbs, often preceded by hyperpathia and spontaneous shooting or lancinating pain. It is caused by several missense mutations in the genes encoding 2 of the 3 subunits of the enzyme serine palmitoyltransferase (SPT). The mutant forms of the enzyme show a shift from their canonical substrate l-serine to the alternative substrate l-alanine. This shift leads to increased formation of neurotoxic deoxysphingolipids (dSLs). Our initial analysis showed that in HEK cells transfected with SPTLC1 mutants, dSL generation was modulated in vitro in the presence of various amino acids. We therefore examined whether in vivo specific amino acid substrate supplementation influenced dSL levels and disease severity in HSAN1. In mice bearing a transgene expressing the C133W SPTLC1 mutant linked to HSAN1, a 10% l-serine–enriched diet reduced dSL levels. l-serine supplementation also improved measures of motor and sensory performance as well as measures of male fertility. In contrast, a 10% l-alanine–enriched diet increased dSL levels and led to severe peripheral neuropathy. In a pilot study with 14 HSAN1 patients, l-serine supplementation similarly reduced dSL levels. These observations support the hypothesis that an altered substrate selectivity of the mutant SPT is key to the pathophysiology of HSAN1 and raise the prospect of l-serine supplementation as a first treatment option for this disorder.

Authors

Kevin Garofalo, Anke Penno, Brian P. Schmidt, Ho-Joon Lee, Matthew P. Frosch, Arnold von Eckardstein, Robert H. Brown, Thorsten Hornemann, Florian S. Eichler

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Figure 7

Effects of supplementation on sciatic nerve morphology.

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Effects of supplementation on sciatic nerve morphology.
C133W transgenic...
C133W transgenic mice were fed diets with 10% l-serine or 10% l-alanine. (A) Experimental design. Red bar, l-alanine supplementation; blue bar, l-serine supplementation; end of bar denotes time of sacrifice. (B) Quantification of unmyelinated axons revealed rescue of large-caliber axons in young l-serine–treated mice (blue) relative to age-matched untreated C133W transgenic animals (dotted black line; data from ref. 13) and young l-alanine–treated mice (red). Arrow indicates relative decrease in large-caliber axons. (C) EM images of unmyelinated axons from l-serine– and l-alanine–fed mice. Scale bars: 500 nm. (D) Myelinated axons in l-serine–treated animals demonstrated a similar trend of preservation of large axons. Dotted black line represent age-matched untreated C133W transgenic animals (data from ref. 13). Arrow indicates relative decrease in large-caliber axons. (E) EM images of myelinated axons from l-serine– and l-alanine–fed mice. Scale bars: 10 μm. (F) Change in myelination patterns after supplementation, assessed by g ratios. Dotted black line represents old untreated C133W transgenic animals (data from ref. 13). Error bars represent SEM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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