Identification and therapeutic rescue of autophagosome and glutamate receptor defects in C9ORF72 and sporadic ALS neurons.
Identification and therapeutic rescue of autophagosome and glutamate receptor defects in C9ORF72 and sporadic ALS neurons.
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C9ORF72 和散发性 ALS 神经元中自噬体和谷氨酸受体缺陷的鉴定和治疗挽救。
DOI：
10.1172/jci.insight.127736
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发表时间：
2019
期刊：
影响因子：
8
通讯作者：
Ichida,JustinK
中科院分区：
文献类型：
--
作者：
Shi,Yingxiao;Hung,Shu-Ting;Rocha,Gabriel;Lin,Shaoyu;Linares,GabrielR;Staats,KimA;Seah,Carina;Wang,Yaoming;Chickering,Michael;Lai,Jesse;Sugawara,Tohru;Sagare,AbhayP;Zlokovic,BerislavV;Ichida,JustinK
肌萎缩侧索硬化症（amyotrophiclateralsclerosis，ALS）是一种病因多样的致死性运动神经元疾病。因此，识别常见的疾病机制和针对这些机制的治疗方法可以显着改善临床结果。为此，我们从C9 ORF 72和散发性ALS患者中开发了诱导运动神经元（iMN）模型，以确定对这些类型病例有效的靶点，这些病例共占约90%的患者。我们发现来自C9 ORF 72和几个散发性ALS患者的iMN具有2个共同的缺陷-受损的自噬体形成和谷氨酸受体的异常积累。此外，我们发现，抗凝缺陷形式的活化蛋白C，3 K3 A-APC，挽救这些缺陷C9 ORF 72和散发性ALS iMN。因此，3 K3 A-APC治疗降低了C9 ORF 72二肽重复蛋白（DPR）水平，恢复了核TDP-43定位，并挽救了C9 ORF 72和散发性ALS iMN的存活。重要的是，3 K3 A-APC还降低谷氨酸受体水平，并在C9 ORF 72功能获得和丧失小鼠模型中挽救体内蛋白质稳态。因此，来自C9 ORF 72的运动神经元和散发性ALS患者的至少一个子集共享自噬体形成和谷氨酸受体稳态的早期缺陷，并且单一治疗方法可能对这些疾病过程有效。
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with diverse etiologies. Therefore, the identification of common disease mechanisms and therapeutics targeting these mechanisms could dramatically improve clinical outcomes. To this end, we developed induced motor neuron (iMN) models from C9ORF72 and sporadic ALS patients to identify targets that are effective against these types of cases, which together comprise approximately 90% of patients. We find that iMNs from C9ORF72 and several sporadic ALS patients share 2 common defects — impaired autophagosome formation and the aberrant accumulation of glutamate receptors. Moreover, we show that an anticoagulation-deficient form of activated protein C, 3K3A-APC, rescues these defects in both C9ORF72 and sporadic ALS iMNs. As a result, 3K3A-APC treatment lowers C9ORF72 dipeptide-repeat protein (DPR) levels, restores nuclear TDP-43 localization, and rescues the survival of both C9ORF72 and sporadic ALS iMNs. Importantly, 3K3A-APC also lowers glutamate receptor levels and rescues proteostasis in vivo in C9ORF72 gain- and loss-of-function mouse models. Thus, motor neurons from C9ORF72 and at least a subset of sporadic ALS patients share early defects in autophagosome formation and glutamate receptor homeostasis and a single therapeutic approach may be efficacious against these disease processes.