Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
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DOI：
10.1038/s41591-021-01346-1
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发表时间：
2021-07
期刊：
影响因子：
82.9
通讯作者：
Bonnemann, Carsten G.
中科院分区：
文献类型：
--
作者：
Mohassel, Payam;Donkervoort, Sandra;Lone, Museer A.;Nalls, Matthew;Gable, Kenneth;Gupta, Sita D.;Foley, A. Reghan;Hu, Ying;Saute, Jonas Alex Morales;Moreira, Ana Lucila;Kok, Fernando;Introna, Alessandro;Logroscino, Giancarlo;Grunseich, Christopher;Nickolls, Alec R.;Pourshafie, Naemeh;Neuhaus, Sarah B.;Saade, Dimah;Gangfuss, Andrea;Koelbel, Heike;Piccus, Zoe;Le Pichon, Claire E.;Fiorillo, Chiara;Ly, Cindy V.;Topf, Ana;Brady, Lauren;Specht, Sabine;Zidell, Aliza;Pedro, Helio;Mittelmann, Eric;Thomas, Florian P.;Chao, Katherine R.;Konersman, Chamindra G.;Cho, Megan T.;Brandt, Tracy;Straub, Volker;Connolly, Anne M.;Schara, Ulrike;Roos, Andreas;Tarnopolsky, Mark;Hoke, Ahmet;Brown, Robert H.;Lee, Chia-Hsueh;Hornemann, Thorsten;Dunn, Teresa M.;Bonnemann, Carsten G.
肌萎缩侧索硬化症(ALS)是一种散发性或遗传性的进行性上、下运动神经元退行性疾病。肌萎缩侧索硬化症的发病年龄、运动神经元变性模式和疾病进展在个体之间差异很大。不同的细胞过程可能推动ALS的发病机制，但单基因直接代谢紊乱与ALS没有因果联系。在这里，我们展示了导致无限制的狮身人面像碱基合成的SPTLC1变体，导致了ALS的单基因形式。我们在7个家系中确定了4个特殊的、主要起作用的SPTLC1变异，表现为儿童期起病的ALS。这些变异破坏了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，标准SPT产物水平升高。值得注意的是，这与SPTLC1变异体形成对比，SPTLC1变异体将SPT氨基酸的使用从丝氨酸转变为丙氨酸，导致脱氧鞘磷脂水平升高，并表现为遗传性感觉和自主神经病变的交替表型。我们定制了小干扰RNA，选择性地针对SPTLC1 ALS等位基因进行降解，保持正常等位基因不变，并在体外使鞘磷脂水平正常化。原发代谢紊乱在肌萎缩侧索硬化症中的作用一直难以捉摸；本研究将过度的鞘磷脂生物合成定义为运动神经元病的基本代谢机制。
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.
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DOI：
10.1073/pnas.0811269106
发表时间：
2009-05-19
影响因子：
11.1
作者：
Han, Gongshe;Gupta, Sita D.;Dunn, Teresa M.
通讯作者：
Dunn, Teresa M.
影响因子：
9.9
作者：
Fridman, Vera;Suriyanarayanan, Saranya;Eichler, Florian
通讯作者：
Eichler, Florian
影响因子：
11.2
作者：
Cudkowicz, ME;McKenna-Yasek, D;Brown, RH
通讯作者：
Brown, RH
影响因子：
4.8
作者：
Gupta, Sita D.;Gable, Kenneth;Harmon, Jeffrey M.
通讯作者：
Harmon, Jeffrey M.
影响因子：
3.5
作者：
Bode, Heiko;Bourquin, Florence;Hornemann, Thorsten
通讯作者：
Hornemann, Thorsten