Overexpression of the Wild-Type SPT1 Subunit Lowers Desoxysphingolipid Levels and Rescues the Phenotype of HSAN1
Overexpression of the Wild-Type SPT1 Subunit Lowers Desoxysphingolipid Levels and Rescues the Phenotype of HSAN1
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DOI：
10.1523/jneurosci.2536-09.2009
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发表时间：
2009-11-18
影响因子：
5.3
通讯作者：
Brown, Robert H., Jr.
中科院分区：
文献类型：
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作者：
Eichler, Florian S.;Hornemann, Thorsten;Brown, Robert H., Jr.
丝氨酸棕榈酰转移酶（SPT）的SPTLC 1亚基突变导致成人发病的遗传性感觉和自主神经病变I型（HSAN 1）。我们以前报道过，携带转基因表达突变SPTLC 1（tgSPTLC 1（C133 W））的小鼠在10个月大时表现出SPT活性降低和痛觉过敏。现在在以后的年龄进行分析，我们发现这些小鼠出现感觉丧失，伴有远端小纤维神经病和外周髓鞘病。当这些小鼠与过表达野生型SPTLC 1的转基因小鼠杂交时，这种表型在很大程度上被逆转，这表明突变SPTLC 1蛋白质不是固有毒性的。SPT活性的简单丧失也不能解释HSAN 1表型，因为杂合SPTLC 1敲除小鼠的SPT活性降低，但其他方面正常。相反，在tgSPTLC 1（C133 W）中存在两个新鉴定的、潜在有害的脱氧鞘氨醇类碱基，但在野生型、双转基因tgSPTLC 1（WT + C133 W）或SPTLC 1（+/-）小鼠中不存在，这表明HSAN 1突变改变了SPT酶的氨基酸选择性，使得棕榈酸酯与丙氨酸和甘氨酸缩合，而不是丝氨酸。这一观察结果与HSAN 1是SPTLC 1中功能获得性突变的结果的假设一致，该突变导致毒性代谢物的积累。
Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT) cause an adult-onset, hereditary sensory, and autonomic neuropathy type I (HSAN1). We previously reported that mice bearing a transgene-expressing mutant SPTLC1 (tgSPTLC1(C133W)) show a reduction in SPT activity and hyperpathia at 10 months of age. Now analyzed at a later age, we find these mice develop sensory loss with a distal small fiber neuropathy and peripheral myelinopathy. This phenotype is largely reversed when these mice are crossed with transgenic mice overexpressing wild-type SPTLC1 showing that the mutant SPTLC1 protein is not inherently toxic. Simple loss of SPT activity also cannot account for the HSAN1 phenotype, since heterozygous SPTLC1 knock-out mice have reduced SPT activity but are otherwise normal. Rather, the presence of two newly identified, potentially deleterious deoxysphingoid bases in the tgSPTLC1(C133W), but not in the wild-type, double-transgenic tgSPTLC1(WT + C133W) or SPTLC1 (+/-) mice, suggests that the HSAN1 mutations alter amino acid selectivity of the SPT enzyme such that palmitate is condensed with alanine and glycine, in addition to serine. This observation is consistent with the hypothesis that HSAN1 is the result of a gain-of-function mutation in SPTLC1 that leads to accumulation of a toxic metabolite.