Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1
Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1
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DOI：
10.1172/jci57549
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发表时间：
2011-12-01
影响因子：
15.9
通讯作者：
Eichler, Florian S.
中科院分区：
文献类型：
--
作者：
Garofalo, Kevin;Penno, Anke;Eichler, Florian S.
遗传性感觉和自主神经病1型（HSAN 1）引起感觉丧失，主要影响下肢，通常伴有痛觉过敏和自发性射击或刺痛。它是由编码丝氨酸棕榈酰转移酶（SPT）的3个亚基中的2个的基因中的几个错义突变引起的。该酶的突变形式显示出从其典型底物L-丝氨酸到替代底物L-丙氨酸的转变。这种转变导致神经毒性脱氧鞘脂（dSL）的形成增加。我们的初步分析表明，在转染SPTLC 1突变体的HEK细胞中，在各种氨基酸的存在下，在体外调节dSL的产生。因此，我们研究了体内特定氨基酸底物补充是否影响HSAN 1中的dSL水平和疾病严重程度。在携带表达与HSAN 1相关的C133 W SPTLC 1突变体的转基因小鼠中，10%L-丝氨酸富集饮食降低了dSL水平。补充L-丝氨酸还改善了运动和感觉性能的测量以及男性生育能力的测量。相比之下，富含10% L-丙氨酸的饮食增加了dSL水平，并导致严重的周围神经病变。在14名HSAN 1患者的初步研究中，L-丝氨酸补充剂同样降低了dSL水平。这些意见支持：突变SPT的改变的底物选择性是HSAN 1的病理生理学的关键的假设，并提高了L-丝氨酸补充作为该疾病的第一治疗选择的前景。
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.