美国国立卫生研究院Carsten G. Bnnemann研究小组在研究中取得进展。他们的研究表明鞘脂合成过多是儿童肌萎缩侧索硬化症 (ALS)的诱因。2021年5月31日，国际学术期刊《自然-医学》发表了这一成果。

在本研究中，研究人员揭示了导致无限鞘氨醇碱基合成的 SPTLC1 变体是造成ALS 的单基因模式。研究人员在七个儿童期 ALS 的家庭中发现了四种特定的、显性 SPTLC1 变体。这些变体破坏了 ORMDL 蛋白对丝氨酸棕榈酰转移酶 (SPT) 的正常稳态调节，导致 SPT 活性不受调控和典型 SPT 产物水平升高。

值得注意的是，这与 SPTLC1 变体形成对比，后者将 SPT 氨基酸底物从丝氨酸转变为丙氨酸，导致脱氧鞘脂水平升高，并产生遗传性感觉和自主神经病变的替代表型。研究人员设计了选择性靶向 SPTLC1 ALS 等位基因降解的小干扰 RNA，其可以维持正常等位基因的完整性并使体外鞘脂水平恢复正常。原发性代谢紊乱在 ALS 中的作用一直难以确定。该研究表明过量鞘脂生物合成是造成运动神经元疾病的基本代谢模式。 

研究人员表示，ALS是一种由散发性或遗传性下运动神经元和上运动神经元紊乱造成的进行性、神经退行性疾病。ALS 患者的发病年龄、运动神经元变性模式和疾病进展差异很大。各种细胞过程可能是 ALS 发病的诱因，但单基因调控的代谢紊乱与 ALS 并没有因果关系。

附：英文原文

Title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis

Author: Payam Mohassel, Sandra Donkervoort, Museer A. Lone, Matthew Nalls, Kenneth Gable, Sita D. Gupta, A. Reghan Foley, Ying Hu, Jonas Alex Morales Saute, Ana Lucila Moreira, Fernando Kok, Alessandro Introna, Giancarlo Logroscino, Christopher Grunseich, Alec R. Nickolls, Naemeh Pourshafie, Sarah B. Neuhaus, Dimah Saade, Andrea Gangfu, Heike Klbel, Zoe Piccus, Claire E. Le Pichon, Chiara Fiorillo, Cindy V. Ly, Ana Tpf, Lauren Brady, Sabine Specht, Aliza Zidell, Helio Pedro, Eric Mittelmann, Florian P. Thomas, Katherine R. Chao, Chamindra G. Konersman, Megan T. Cho, Tracy Brandt, Volker Straub, Anne M. Connolly, Ulrike Schara, Andreas Roos, Mark Tarnopolsky, Ahmet Hke, Robert H. Brown, Chia-Hsueh Lee, Thorsten Hornemann, Teresa M. Dunn, Carsten G. Bnnemann

Issue&Volume: 2021-05-31

Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease of the lower and upper motor neurons with sporadic or hereditary occurrence. Age of onset, pattern of motor neuron degeneration and disease progression vary widely among individuals with ALS. Various cellular processes may drive ALS pathomechanisms, but a monogenic direct metabolic disturbance has not been causally linked to ALS. Here we show SPTLC1 variants that result in unrestrained sphingoid base synthesis cause a monogenic form of ALS. We identified four specific, dominantly acting SPTLC1 variants in seven families manifesting as childhood-onset ALS. These variants disrupt the normal homeostatic regulation of serine palmitoyltransferase (SPT) by ORMDL proteins, resulting in unregulated SPT activity and elevated levels of canonical SPT products. Notably, this is in contrast with SPTLC1 variants that shift SPT amino acid usage from serine to alanine, result in elevated levels of deoxysphingolipids and manifest with the alternate phenotype of hereditary sensory and autonomic neuropathy. We custom designed small interfering RNAs that selectively target the SPTLC1 ALS allele for degradation, leave the normal allele intact and normalize sphingolipid levels in vitro. The role of primary metabolic disturbances in ALS has been elusive; this study defines excess sphingolipid biosynthesis as a fundamental metabolic mechanism for motor neuron disease. Clinical and genetic evaluation of individuals with childhood-onset amyotrophic lateral sclerosis identifies a new monogenic cause for early-onset ALS and proposes a specific metabolic mechanism leading to motor neuron disease via sphingolipid excess.

DOI: 10.1038/s41591-021-01346-1

Source: https://www.nature.com/articles/s41591-021-01346-1