Syeda and colleagues used an elegant combination of genetics, meticulous clinical evaluation and cell biology to demonstrate that disrupting serine palmitoyl transferase (SPT) can cause amyotrophic lateral sclerosis (ALS) in very young children.1 SPT is the initial rate-limiting step in sphingolipid biosynthesis, joining serine and palmitoyl CoA in a decarboxylating condensation reaction that ultimately creates ceramide, sphingosine, glycosphingolipids and gangliosides.2 SPT resides in the endoplasmic reticulum membrane as a dimer of two subunits, SPTLC1 and SPTLC2, which are in turn attached to two small subunits ssSPTa and ssSPTb that activate enzyme activity and orosomucoid-like proteins (ORMDLs) that repress SPT activity to ensure sphingolipid homeostasis. Resultant sphingolipids are subsequently processed through the Golgi apparatus and inserted into plasma membranes where they are involved in multiple signalling pathways including those that sometimes cause opposing effects. For example, ceramide frequently induces apoptosis in cells, whereas sphingosine1-phosphate has anti-apoptotic effects. Relative levels of sphingolipids are tightly regulated, and disturbances in these levels have been associated with multiple pathological conditions including cancers, heart …

中文翻译：

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遗传学、细胞生物学和 ALS 的新机制

Syeda 及其同事巧妙地结合了遗传学、细致的临床评估和细胞生物学，证明破坏丝氨酸棕榈酰转移酶 (SPT) 可导致幼儿患肌萎缩侧索硬化症 (ALS)。1 SPT 是鞘脂的初始限速步骤生物合成，在脱羧缩合反应中加入丝氨酸和棕榈酰辅酶A，最终产生神经酰胺、鞘氨醇、鞘糖脂和神经节苷脂。2 SPT 作为两个亚基 SPTLC1 和 SPTLC2 的二聚体存在于内质网膜中，这两个亚基又连接到两个小亚基上。激活酶活性的 ssSPTa 和 ssSPTb 亚基以及抑制 SPT 活性以确保鞘脂稳态的类乳粘蛋白 (ORMDL)。所得的鞘脂随后通过高尔基体进行处理并插入质膜中，参与多种信号传导途径，包括有时会引起相反作用的信号传导途径。例如，神经酰胺经常诱导细胞凋亡，而 1-磷酸鞘氨醇则具有抗凋亡作用。鞘脂的相对水平受到严格调节，这些水平的紊乱与多种病理状况有关，包括癌症、心脏病……