Substrate Reduction Therapy Reverses Mitochondrial, mTOR, and Autophagy Alterations in a Cell Model of Gaucher Disease.
Substrate Reduction Therapy Reverses Mitochondrial, mTOR, and Autophagy Alterations in a Cell Model of Gaucher Disease.
复制标题
底物还原疗法会逆转高刺病细胞模型中的线粒体，mTOR和自噬改变。
作者：
Peng Y;Liou B;Lin Y;Fannin V;Zhang W;Feldman RA;Setchell KDR;Grabowski GA;Sun Y
底物还原疗法（SRT）在临床上充分管理戈谢病（GD）的内脏表现，但对脑部疾病没有直接影响。为了了解SRT在GD治疗中的分子基础，我们在来源于Gba敲除（Gba-/-）小鼠模型的永生化神经元细胞系中评估了SRT的功效和潜在机制。Gba-/-神经元积累底物、葡萄糖神经酰胺和葡萄糖鞘氨醇。细胞增殖减少与溶酶体和自噬改变、线粒体功能降低和mTORC 1通路激活相关。用venglustat类似物GZ 452（一种中枢神经系统可及的SRT）处理Gba-/-神经元，使这些神经元及其分离的线粒体中的葡萄糖神经酰胺水平正常化。在处理的Gba-/-神经元中，增大的溶酶体减少，伴随着自噬空泡减少。GZ 452处理可提高线粒体膜电位和耗氧率。此外，GZ 452减少了mTORC 1通路中选定蛋白的过度活性，并改善了Gba-/-神经元的细胞增殖。这些发现强化了底物积累对神经元中线粒体、自噬和mTOR的不利影响。SRT对GD的线粒体和自噬-溶酶体途径的作用揭示了一种新的拯救机制。这些结果表明线粒体和mTORC 1复合物是治疗GD的潜在治疗靶点。
Substrate reduction therapy (SRT) in clinic adequately manages the visceral manifestations in Gaucher disease (GD) but has no direct effect on brain disease. To understand the molecular basis of SRT in GD treatment, we evaluated the efficacy and underlying mechanism of SRT in an immortalized neuronal cell line derived from a Gba knockout (Gba-/-) mouse model. Gba-/- neurons accumulated substrates, glucosylceramide, and glucosylsphingosine. Reduced cell proliferation was associated with altered lysosomes and autophagy, decreased mitochondrial function, and activation of the mTORC1 pathway. Treatment of the Gba-/- neurons with venglustat analogue GZ452, a central nervous system-accessible SRT, normalized glucosylceramide levels in these neurons and their isolated mitochondria. Enlarged lysosomes were reduced in the treated Gba-/- neurons, accompanied by decreased autophagic vacuoles. GZ452 treatment improved mitochondrial membrane potential and oxygen consumption rate. Furthermore, GZ452 diminished hyperactivity of selected proteins in the mTORC1 pathway and improved cell proliferation of Gba-/- neurons. These findings reinforce the detrimental effects of substrate accumulation on mitochondria, autophagy, and mTOR in neurons. A novel rescuing mechanism of SRT was revealed on the function of mitochondrial and autophagy–lysosomal pathways in GD. These results point to mitochondria and the mTORC1 complex as potential therapeutic targets for treatment of GD.
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DOI：
10.1196/annals.1344.021
发表时间：
2005-01-01
期刊：
NEUROPROTECTIVE AGENTS
影响因子：
--
作者：
Chua, ZT;Sun, Y;Qi, XY
通讯作者：
Qi, XY
影响因子：
12.7
作者：
CONRADI, NG;SOURANDER, P;ERIKSON, A
通讯作者：
ERIKSON, A
DOI：
10.1124/jpet.112.192138
发表时间：
2012-09-01
影响因子：
3.5
作者：
Johri, Ashu;Beal, M. Flint
通讯作者：
Beal, M. Flint
影响因子：
3.5
作者：
Awad, Ola;Sarkar, Chinmoy;Feldman, Ricardo A.
通讯作者：
Feldman, Ricardo A.
影响因子：
9.8
作者：
Koprivica, V;Stone, DL;Sidransky, E
通讯作者：
Sidransky, E