Genetic ablation of acid ceramidase in Krabbe disease confirms the psychosine hypothesis and identifies a new therapeutic target
Genetic ablation of acid ceramidase in Krabbe disease confirms the psychosine hypothesis and identifies a new therapeutic target
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DOI：
10.1073/pnas.1912108116
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发表时间：
2019-10-01
影响因子：
11.1
通讯作者：
Sands, Mark S.
中科院分区：
文献类型：
--
作者：
Li, Yedda;Xu, Yue;Sands, Mark S.
婴儿球样细胞脑白质营养不良（GLD，Krabbe病）是一种致命的脱髓鞘疾病引起的缺陷，在溶酶体酶半乳糖神经酰胺酶（GALC）。GALC缺乏导致细胞毒性糖脂、半乳糖基鞘氨醇（精神病）的积累。补充证据表明，精神病是通过合成代谢途径合成的。在这里，我们表明，而不是精神病是通过酸性神经酰胺酶（ACDase）的半乳糖神经酰胺的脱酰作用分解代谢产生的。这种反应将GALC缺乏与精神病积累分开，使我们能够测试长期存在的“精神病假说”。“我们证明，在GALC缺陷的人类GLD（抽搐）小鼠模型中，ACDase活性的遗传丧失（法伯病）消除了精神病积累并治愈了GLD。这些数据表明，ACDase可能是Krabbe患者底物减少治疗（SRT）的靶点。我们发现，ACDase活性与卡莫氟的药理学抑制显着降低了从Krabbe患者的细胞中的精神病积累和抽搐（Twi）小鼠的寿命。先前在Twi小鼠中进行的SRT实验利用了L-环丝氨酸，其抑制了psychosine合成上游几个步骤的酶，从而改变了其他重要脂质的平衡。直接抑制ACDase的药物可能具有更可接受的安全性特征，因为它们的机制接近于精神碱生物合成。总之，这些数据澄清了我们对psychosine合成的理解，证实了长期以来的psychosine假说，并为发现安全有效的ACDase抑制剂以治疗Krabbe病提供了动力。
Infantile globoid cell leukodystrophy (GLD, Krabbe disease) is a fatal demyelinating disorder caused by a deficiency in the lysosomal enzyme galactosylceramidase (GALC). GALC deficiency leads to the accumulation of the cytotoxic glycolipid, galactosylsphingosine (psychosine). Complementary evidence suggested that psychosine is synthesized via an anabolic pathway. Here, we show instead that psychosine is generated catabolically through the deacylation of galactosylceramide by acid ceramidase (ACDase). This reaction uncouples GALC deficiency from psychosine accumulation, allowing us to test the long-standing "psychosine hypothesis." We demonstrate that genetic loss of ACDase activity (Farber disease) in the GALC-deficient mouse model of human GLD (twitcher) eliminates psychosine accumulation and cures GLD. These data suggest that ACDase could be a target for substrate reduction therapy (SRT) in Krabbe patients. We show that pharmacological inhibition of ACDase activity with carmofur significantly decreases psychosine accumulation in cells from a Krabbe patient and prolongs the life span of the twitcher (Twi) mouse. Previous SRT experiments in the Twi mouse utilized L-cycloserine, which inhibits an enzyme several steps upstream of psychosine synthesis, thus altering the balance of other important lipids. Drugs that directly inhibit ACDase may have a more acceptable safety profile due to their mechanistic proximity to psychosine biogenesis. In total, these data clarify our understanding of psychosine synthesis, confirm the long-held psychosine hypothesis, and provide the impetus to discover safe and effective inhibitors of ACDase to treat Krabbe disease.