Neuron-based high-content assay and screen for CNS active mitotherapeutics
Neuron-based high-content assay and screen for CNS active mitotherapeutics
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DOI：
10.1126/sciadv.aaw8702
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发表时间：
2020-01-01
期刊：
影响因子：
13.6
通讯作者：
Davis, Ronald L.
中科院分区：
文献类型：
--
作者：
Varkuti, Boglarka H.;Kepiro, Miklos;Davis, Ronald L.
线粒体动力学和功能受损是许多神经和精神疾病的标志，但尚未报道使用神经元直接筛选线粒体治疗药物。我们开发了一种使用原代神经元的多重高内涵筛选测定法，并鉴定了 67 种神经元有丝分裂 (MnM) 的小分子调节剂。大多数增加线粒体含量、长度和/或健康的 MnM 也增加了线粒体功能，而不改变神经突的生长。 MnM 的一个子集可保护原代神经元中的线粒体免受 A.(1-42) 毒性、谷氨酸毒性和氧化应激增加的影响。一些 MnM 被证明可以直接靶向线粒体。顶部的 MnM 还增加了海马神经元的突触活性，并被证明在体内有效，在给小鼠施用该化合物后，增加了脑线粒体的呼吸速率。我们的结果提供了一个直接查询神经元有丝分裂过程的平台、线粒体动力学和功能的小分子调节剂的集合以及有丝分裂治疗的候选分子。
Impaired mitochondrial dynamics and function are hallmarks of many neurological and psychiatric disorders, but direct screens for mitotherapeutics using neurons have not been reported. We developed a multiplexed and high-content screening assay using primary neurons and identified 67 small-molecule modulators of neuronal mitostasis (MnMs). Most MnMs that increased mitochondrial content, length, and/or health also increased mitochondrial function without altering neurite outgrowth. A subset of MnMs protected mitochondria in primary neurons from A.(1-42) toxicity, glutamate toxicity, and increased oxidative stress. Some MnMs were shown to directly target mitochondria. The top MnM also increased the synaptic activity of hippocampal neurons and proved to be potent in vivo, increasing the respiration rate of brain mitochondria after administering the compound to mice. Our results offer a platform that directly queries mitostasis processes in neurons, a collection of small-molecule modulators of mitochondrial dynamics and function, and candidate molecules for mitotherapeutics.