Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by impaired motor coordination due to neurological defects and cerebellar dysfunction caused by the accumulation of cholesterol in endolysosomes. Besides the increase in lysosomal cholesterol, mitochondria are also enriched in cholesterol, which leads to decreased membrane fluidity, impaired mitochondrial function and loss of GSH, and has been shown to contribute to the progression of NPC disease. S-Adenosyl--methionine (SAM) regulates membrane physical properties through the generation of phosphatidylcholine (PC) from phosphatidylethanolamine (PE) methylation and functions as a GSH precursor by providing cysteine in the transsulfuration pathway. However, the role of SAM in NPC disease has not been investigated. Here we report that mice exhibit decreased brain SAM levels but unchanged S-adenosyl--homocysteine content and lower expression of . Brain mitochondria from mice display decreased mitochondrial GSH levels and liquid chromatography-high resolution mass spectrometry analysis reveal a lower PC/PE ratio in mitochondria, contributing to increased mitochondrial membrane order. treatment of mice with SAM restores SAM levels in mitochondria, resulting in increased PC/PE ratio, mitochondrial membrane fluidity and subsequent replenishment of mitochondrial GSH levels. SAM treatment improves the decline of locomotor activity, increases Purkinje cell survival in the cerebellum and extends the average and maximal life spam of mice. These findings identify SAM as a potential therapeutic approach for the treatment of NPC disease.

中文翻译：

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S-腺苷-L-蛋氨酸恢复脑线粒体膜流动性和 GSH 含量，改善尼曼-匹克 C 型疾病


C 型尼曼-皮克病 (NPC) 是一种溶酶体贮积症，其特征是由于神经系统缺陷和内溶酶体中胆固醇积累引起的小脑功能障碍导致运动协调受损。除了溶酶体胆固醇增加外，线粒体也富含胆固醇，这会导致膜流动性降低、线粒体功能受损和谷胱甘肽损失，并已被证明有助于鼻咽癌疾病的进展。 S-腺苷-蛋氨酸 (SAM) 通过磷脂酰乙醇胺 (PE) 甲基化生成磷脂酰胆碱 (PC) 来调节膜物理特性，并通过在转硫途径中提供半胱氨酸来充当 GSH 前体。然而，SAM 在 NPC 疾病中的作用尚未得到研究。在此，我们报告小鼠大脑 SAM 水平降低，但 S-腺苷-同型半胱氨酸含量不变，且 .小鼠脑线粒体显示线粒体 GSH 水平降低，液相色谱-高分辨率质谱分析显示线粒体中 PC/PE 比率较低，导致线粒体膜秩序增加。用 SAM 治疗小鼠可以恢复线粒体中的 SAM 水平，从而增加 PC/PE 比率、线粒体膜流动性以及随后补充线粒体 GSH 水平。 SAM 治疗改善了运动活性的下降，增加了小脑中浦肯野细胞的存活率，并延长了小鼠的平均和最大寿命。这些发现表明 SAM 是治疗鼻咽癌疾病的潜在治疗方法。