Ceramide contributes to pathogenesis and may be targeted for therapy in VCP inclusion body myopathy.
Ceramide contributes to pathogenesis and may be targeted for therapy in VCP inclusion body myopathy.
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DOI：
10.1093/hmg/ddaa248
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发表时间：
2020-12
影响因子：
3.5
通讯作者：
Lan Weiss;K. Jung;A. Nalbandian;K. Llewellyn;Howard Yu;Lac Ta;I. Chang;M. Migliore;Erica Squire;Faizy Ahmed;D. Piomelli;V. Kimonis
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文献类型：
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作者：
Lan Weiss;K. Jung;A. Nalbandian;K. Llewellyn;Howard Yu;Lac Ta;I. Chang;M. Migliore;Erica Squire;Faizy Ahmed;D. Piomelli;V. Kimonis
背景/目的敲入纯合子VCPR155H/R155H突变小鼠是一种致死性的Valosin含蛋白相关包涵体肌病、Paget病、额颞叶痴呆和肌萎缩侧索硬化症的动物模型。与野生型对照相比，突变小鼠骨骼肌中神经酰胺(D18：1/16：0)水平升高。此外，暴露在富含脂肪的饮食中可以逆转这些突变小鼠的致死率，改善肌病，并使神经酰胺水平正常化，这表明脂类信号转导功能障碍在疾病发病机制中起着关键作用。在这里，我们研究了神经酰胺在VCP疾病中的潜在作用，我们使用药物来控制VCP突变小鼠和VCP患者成肌细胞培养中神经酰胺的水平。方法用神经酰胺降解抑制剂ARN082处理野生型VCPR155H/+和VCPR155H/R155H小鼠成肌细胞以及患者诱导的多能干细胞(IPSCs)，作为原理验证。通过丝氨酸棕榈酰辅酶A转移酶生物合成神经酰胺的三种不同的化学抑制剂(L-环丝氨酸、肉豆蔻素或ARN14494)被用作减少成肌细胞中神经酰胺的治疗策略。结果酸性神经酰胺酶抑制剂ARN082使细胞神经酰胺水平升高，病理增强。相反，神经酰胺生物合成的抑制剂L-环丝氨酸、豆蔻菌素和ARN14494减少了神经酰胺的生产。这些结果表明神经酰胺介导的信号转导是VCP疾病发病机制的关键因素，并提示通过阻断神经酰胺生物合成来操纵这一途径可能对患有这种疾病的患者起到有益的作用。结论神经酰胺途径在VCP的发病机制中起关键作用，神经酰胺生物合成的小分子抑制剂可能对VCP及相关的神经退行性疾病有治疗作用。
BACKGROUND/OBJECTIVE Knock-in homozygote VCPR155H/R155H mutant mice are a lethal model of Valosin Containing Protein (VCP)-associated Inclusion Body Myopathy, Paget disease of bone, frontotemporal dementia, and amyotropic lateral sclerosis. Ceramide (d18:1/16:0) levels are elevated in skeletal muscle of the mutant mice, compared to wild-type controls. Moreover, exposure to a lipid-enriched diet reverses lethality, improves myopathy and normalizes ceramide levels in these mutant mice, suggesting that dysfunctions in lipid-derived signaling are critical to disease pathogenesis. Here, we investigated the potential role of ceramide in VCP disease using pharmacological agents that manipulate the ceramide levels in myoblast cultures from VCP mutant mice and VCP patients. METHODS Myoblasts from wild-type, VCPR155H/+ and VCPR155H/R155H mice, as well as patient induced pluripotent stem cells (iPSCs), were treated with an inhibitor of ceramide degradation to increase ceramide via acid ceramidase (ARN082) for proof of principle. Three chemically distinct inhibitors of ceramide biosynthesis via serine palmitoyl-CoA transferase (L-cycloserine, myriocin or ARN14494) used as a therapeutic strategy to reduce ceramide in myoblasts. RESULTS Acid ceramidase inhibitor, ARN082, elevated cellular ceramide levels and concomitantly enhanced pathology. Conversely inhibitors of ceramide biosynthesis L-cycloserine, myriocin and ARN14494 reduced ceramide production. The results point to ceramide-mediated signaling as a key contributor to pathogenesis in VCP disease, and suggests that manipulating this pathway by blocking ceramide biosynthesis might exert beneficial effects in patients with this condition. CONCLUSION The ceramide pathway appears to be critical in VCP pathogenesis, and small-molecule inhibitors of ceramide biosynthesis might provide therapeutic benefit in VCP and, related neurodegenerative diseases.