Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein.
Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein.
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DOI：
10.7554/elife.29123
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发表时间：
2017-12-26
期刊：
影响因子：
7.7
通讯作者：
Marugan JJ
中科院分区：
文献类型：
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作者：
Al-Ramahi I;Giridharan SSP;Chen YC;Patnaik S;Safren N;Hasegawa J;de Haro M;Wagner Gee AK;Titus SA;Jeong H;Clarke J;Krainc D;Zheng W;Irvine RF;Barmada S;Ferrer M;Southall N;Weisman LS;Botas J;Marugan JJ
亨廷顿病（HD）致病基因的发现促进了许多努力，以揭示降低突变亨廷顿蛋白（mHtt）水平的细胞途径，并潜在地阻止HD相关神经缺陷的出现。使用基于细胞的致病性亨廷顿蛋白表达模型，我们鉴定了一类通过选择性抑制脂质激酶PIP4Kγ来保护细胞的化合物。PIP4Kγ的药理学抑制或敲低调节细胞内磷脂酰肌醇（PI）物质之间的平衡，并增加基础自噬，减少人类患者成纤维细胞中mHtt蛋白的总量和神经元中的聚集体。在亨廷顿病的两个果蝇模型中，分别使用运动表现和视网膜变性测定评估，PIP4 K的遗传敲低改善了神经元功能障碍和变性。总之，这些结果表明，PIP4 K γ是一种可药物化的靶标，其抑制增强了生产性自噬和mHtt蛋白水解，揭示了用于治疗亨廷顿病以及潜在地用于其他神经退行性疾病的有用的药理学干预点。
The discovery of the causative gene for Huntington’s disease (HD) has promoted numerous efforts to uncover cellular pathways that lower levels of mutant huntingtin protein (mHtt) and potentially forestall the appearance of HD-related neurological defects. Using a cell-based model of pathogenic huntingtin expression, we identified a class of compounds that protect cells through selective inhibition of a lipid kinase, PIP4Kγ. Pharmacological inhibition or knock-down of PIP4Kγ modulates the equilibrium between phosphatidylinositide (PI) species within the cell and increases basal autophagy, reducing the total amount of mHtt protein in human patient fibroblasts and aggregates in neurons. In two Drosophila models of Huntington’s disease, genetic knockdown of PIP4K ameliorated neuronal dysfunction and degeneration as assessed using motor performance and retinal degeneration assays respectively. Together, these results suggest that PIP4Kγ is a druggable target whose inhibition enhances productive autophagy and mHtt proteolysis, revealing a useful pharmacological point of intervention for the treatment of Huntington’s disease, and potentially for other neurodegenerative disorders.