Mutant SPTLC1 dominantly inhibits serine palmitoyltransferase activity in vivo and confers an age-dependent neuropathy
Mutant SPTLC1 dominantly inhibits serine palmitoyltransferase activity in vivo and confers an age-dependent neuropathy
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DOI：
10.1093/hmg/ddi380
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发表时间：
2005-11-15
影响因子：
3.5
通讯作者：
Brown, RH
中科院分区：
文献类型：
--
作者：
McCampbell, A;Truong, D;Brown, RH
参与鞘脂代谢和运输的酶的突变引起各种神经系统疾病，但分子病理生理学的细节仍然不清楚。SPTLC1编码丝氨酸棕榈酰转移酶（SPT）的一个亚基，SPT是鞘脂合成的限速酶。SPTLC1突变导致遗传性感觉和自主神经病变（I型）（HSAN 1），一种成人发病的常染色体显性神经病变。HSAN 1患者的SPT活性降低。突变体SPTLC1在酵母和哺乳动物细胞培养物中的表达主要抑制SPT活性。我们创建了普遍过表达野生型（SPTLC1（WT））或突变型SPTLC1（SPTLC1（C133W））的转基因小鼠品系。我们在这里报告SPTLC1（C133W）小鼠出现年龄依赖性体重减轻和轻度感觉和运动障碍。老年SPTLC1（C133W）小鼠在脊髓腹根中失去了大的有髓轴突，并表现出髓鞘变薄。在背根中也有大的有髓轴突的损失，尽管无髓纤维被保留。在背根神经节中，IB4染色减弱，而损伤诱导的转录因子ATF3的表达增加。这些小鼠代表了一种新的周围神经病变小鼠模型，并证实突变SPT和神经元功能障碍之间的联系。
Mutations in enzymes involved in sphingolipid metabolism and trafficking cause a variety of neurological disorders, but details of the molecular pathophysiology remain obscure. SPTLC1 encodes one subunit of serine palmitoyltransferase (SPT), the rate-limiting enzyme in sphingolipid synthesis. Mutations in SPTLC1 cause hereditary sensory and autonomic neuropathy (type I) (HSAN1), an adult onset, autosomal dominant neuropathy. HSAN1 patients have reduced SPT activity. Expression of mutant SPTLC1 in yeast and mammalian cell cultures dominantly inhibits SPT activity. We created transgenic mouse lines that ubiquitously overexpress either wild-type (SPTLC1(WT)) or mutant SPTLC1 (SPTLC1(C133W)). We report here that SPTLC1(C133W) mice develop age-dependent weight loss and mild sensory and motor impairments. Aged SPTLC1(C133W) mice lose large myelinated axons in the ventral root of the spinal cord and demonstrate myelin thinning. There is also a loss of large myelinated axons in the dorsal roots, although the unmyelinated fibers are preserved. In the dorsal root ganglia, IB4 staining is diminished, whereas expression of the injury-induced transcription factor ATF3 is increased. These mice represent a novel mouse model of peripheral neuropathy and confirm the link between mutant SPT and neuronal dysfunction.