Discoidin Domain Receptor 1 is a therapeutic target for neurodegenerative diseases
Discoidin Domain Receptor 1 is a therapeutic target for neurodegenerative diseases
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DOI：
10.1093/hmg/ddaa177
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发表时间：
2020-09-01
影响因子：
3.5
通讯作者：
Moussa, Charbel
中科院分区：
文献类型：
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作者：
Fowler, Alan J.;Hebron, Michaeline;Moussa, Charbel
盘状蛋白结构域受体 (DDR) 在神经退行性疾病中的作用尚不清楚。 DDR 在阿尔茨海默病和帕金森病 (PD) 中表达上调，而 DDR 敲除可降低神经毒性蛋白水平。在这里，我们展示了有效且优先的 DDR1 抑制剂可降低体外和体内神经毒性蛋白水平。在用 cy-synuclein 攻击的小鼠模型中，部分或完全删除或抑制 DDR1 可增加自噬并减少炎症和神经毒性蛋白。在患有或不患有痴呆和路易体痴呆的PD中观察到控制炎症、神经元损伤、自噬和囊泡运输基因的脑脊液microRNA的显着变化，但这些变化在用DDR1抑制剂尼罗替尼治疗后减弱或逆转。总的来说，这些数据表明 DDR1 调节自噬并减少神经毒性蛋白和炎症，是神经退行性疾病的治疗靶点。
The role of Discoidin Domain Receptors (DDRs) is poorly understood in neurodegeneration. DDRs are upregulated in Alzheimer's and Parkinson's disease (PD), and DDRs knockdown reduces neurotoxic protein levels. Here we show that potent and preferential DDR1 inhibitors reduce neurotoxic protein levels in vitro and in vivo. Partial or complete deletion or inhibition of DDR1 in a mouse model challenged with cy-synuclein increases autophagy and reduces inflammation and neurotoxic proteins. Significant changes of cerebrospinal fluid microRNAs that control inflammation, neuronal injury, autophagy and vesicular transport genes are observed in PD with and without dementia and Lewy body dementia, but these changes are attenuated or reversed after treatment with the DDR1 inhibitor, nilotinib. Collectively, these data demonstrate that DDR1 regulates autophagy and reduces neurotoxic proteins and inflammation and is a therapeutic target in neurodegeneration.