1-DEOXYDIHYDROCERAMIDES IN HEREDITARY SENSORY & AUTONOMIC NEUROPATHY TYPE I

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 遗传性感觉和自主神经病变I型(HSAN1)是由编码丝氨酸棕榈酰转移酶(SPT)亚单位的SPTLC1基因的错义突变引起的。我们最近发现了两种新的脱氧狮身人面像碱基(DSB)，脱氧鞘氨醇(DoxSA)和脱氧甲基鞘氨酸碱(DoxMeSA)，它们聚集在HSAN1患者和携带转基因表达突变SPTLC1的小鼠的血浆中。突变的酶似乎与其正常的首选底物丝氨酸的反应性显著降低，而与丙氨酸和甘氨酸的反应性混杂地增加。与丝氨酸缺乏羟基相比，这两种氨基酸在突变动物中发生了转变，形成了不能在氨基上磷酸化的DSB。这些观察表明，HSAN1病毒病理生理学的关键是酶的底物选择性改变，从而推论这一假设可以通过大量作用来克服，即在小鼠和人类体内用远远超过丙氨酸和甘氨酸的L丝氨酸来淹没酶环境。为了支持这一假设，在食用10%丝氨酸强化饮食的突变小鼠中，DoxSA水平在2至4天内降低了5倍。一旦节食，这些小鼠在感觉(机械敏感度)和运动表现(转盘)两个指标上都显著防止了神经退化。在对14名人类HSAN1患者的初步研究中，我们观察到L-丝氨酸补充剂具有类似的显著效果。目前尚不清楚DoxSA和DoxMeSA是否具有神经毒性或其他代谢物参与其中。因此，我们对15名对照组和14名HSAN1患者(接受非L丝氨酸治疗)进行了脱氧二氢神经酰胺的测定，以评估DoxSA的这种代谢产物是否可能是在我们的小鼠中看到的病理的罪魁祸首。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Hereditary sensory and autonomic neuropathy type I (HSAN1) is caused by missense mutations in the SPTLC1 gene encoding a subunit of the enzyme serine palmitoyltransferase (SPT). We recently identified two novel deoxysphingoid bases (DSB), deoxysphinganine (DoxSA) and deoxymethylsphinganine (DoxMeSA), that accumulate in plasma of HSAN1 patients as well as of mice bearing a transgene expressing mutant SPTLC1. It appears that the mutant enzyme has a dramatically reduced reactivity with its normal preferred substrate serine and a promiscuously increased reactivity with alanine and glycine. In that these two amino acids, in contrast to serine lack hydroxyl groups, there is a shift in the mutant animals to formation of DSB that cannot be phosphorylated at the amino OH group. These observations suggest the hypothesis that a key to the pathophysiology of HSAN1 is the altered substrate selectivity of the enzyme with the corollary hypothesis that this could be overcome by mass action, that is, by flooding the enzyme environment in both mice and humans with L-serine, greatly in excess of alanine and glycine. In support of this hypothesis, in mutant mice on a 10% serine enriched diet DoxSA levels were reduced by 5-fold within 2 to 4 days. Once on the diet, these mice were dramatically protected from neurodegeneration on both measures of sensory (mechanical sensitivity) and motor performance (rotorod). In a pilot study of 14 human HSAN1 patients, we observed similar dramatic effects of L-serine supplementation. It is currently nuclear whether DoxSA and DoxMeSA are neurotoxic or other metabolites are involved. We have therefore undertaken the measurement of deoxydihydroceramides in 15 controls and 14 HSAN1 patients (on a off L-serine treatment) to assess whether this metabolic product of DoxSA may be the culprit of pathology seen in our mice.