Novel Pathways to Excitotoxicity in Multiple Sclerosis Caused by Inappropriate Intrusion of an Axonal Mitochondrial Anchor Syntaphilin into Dendrites

轴突线粒体锚亲合蛋白不适当侵入树突引起的多发性硬化症兴奋性毒性的新途径

基本信息

批准号：
10641019
负责人：
SHING Yan CHIU
金额：
$ 39.98万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-06-30
项目状态：
未结题

项目摘要

The premise of this RO1 is to test a R21-derived hypothesis that inappropriate intrusion of a mitochondrial anchoring protein, Syntaphilin (SNPH), into neuronal dendrites is harmful in Progressive Multiple Sclerosis (MS). Progressive MS refers to the late-phase of MS and currently this disease phase has no treatments. SNPH is normally expressed only in axons. Surprisingly, under support from a R21, we discovered that SNPH intrudes into dendrites of Purkinje cells in the cerebellum and causes excitotoxicity in a rodent model (Shiverer) for Progressive MS (Joshi et al., 2019, Cell Reports, Article In Press 15th October). This discovery suggests that targeting SNPH to block intrusion into dendrites is a novel treatment for Progressive MS. In this follow-up RO1, we will address three important questions raised by our R21 discovery highly relevant to the basic science and clinical aspect of MS. In Aim #1, we will test the hypothesis that the pathology of dendritic SNPH intrusion in the grey matter is de-coupled from the pathology of white matter. We will test this hypothesis by showing that curing white matter pathology in the Shiverer model (by genetically suppressing axonal degeneration and by remyelination therapy) will not prevent the pathology of dendritic SNPH intrusion. In Aim #2, we will test the hypothesis that dendritic SNPH intrusion causes excitotoxicity by biasing the activation of NMDA receptors towards the pro-death, extra-synaptic NMDA receptors. In Aim #3, we will test the hypothesis that the glutamate released by synaptic activity, when it spills over to the extra-synaptic region as exacerbated by dysfunctional glutamate uptake, constitutes an early glutamate signaling cascade that triggers dendritic SNPH intrusion. Conclusion – SNPH is a key protein that controls mitochondrial movement with multi-faceted effects on neuronal behaviors in health and disease. Since the cloning of SNPH in 2000, the studies of SNPH in neurons have been exclusively in axons. The Novelty of this RO1 is a paradigm shift to pioneer the study of SNPH in dendrites. The Translational Significance is the surprising discovery that dendritic SNPH mediates excitotoxicity in Progressive MS, thereby opening up new insights to treat MS in this incurable late-phase.

该 RO1 的前提是测试源自 R21 的假设，即线粒体的不当侵入锚定蛋白 Syntaphilin (SNPH) 进入神经元树突对进行性多发性硬化症有害 (MS) 进行性多发性硬化症是指多发性硬化症的晚期阶段，目前该疾病阶段尚无治疗方法。 SNPH 通常仅在轴突中表达，令人惊讶的是，在 R21 的支持下，我们发现 SNPH。侵入小脑浦肯野细胞的树突并在啮齿动物模型中引起兴奋性毒性（颤抖症）进展性多发性硬化症（Joshi 等人，2019 年，Cell Reports，10 月 15 日出版的文章）。在本次后续研究中，我们发现靶向 SNPH 来阻止树突侵入是治疗进展性多发性硬化症的一种新方法。 RO1，我们将解决 R21 发现所提出的三个重要问题，这些问题与基本原理高度相关 MS 的科学和临床方面在目标 1 中，我们将检验树突状 SNPH 的病理学假设灰质的侵入与白质的病理学脱钩，我们将通过以下方式检验这一假设。表明可以治愈 Shiverer 模型中的白质病理（通过基因抑制轴突变性和髓鞘再生治疗）不会阻止树突 SNPH 侵入的病理学。 #2，我们将测试树突 SNPH 侵入通过偏向激活而引起兴奋性毒性的假设 NMDA 受体朝向促死亡、突触外 NMDA 受体在目标 #3 中，我们将检验假设。谷氨酸通过释放突触活动，当它溢出到突触外区域时加剧通过功能失调的谷氨酸摄取，构成早期谷氨酸信号级联，触发树突 SNPH 入侵。结论 – SNPH 是控制线粒体运动的关键蛋白，对线粒体运动具有多方面的影响健康和疾病中的神经元行为自 2000 年 SNPH 克隆以来，SNPH 在神经元中的研究。 RO1 的新颖性是对 SNPH 研究的先锋性转变。树突的翻译意义是树突 SNPH 介导的令人惊讶的发现。进行性多发性硬化症中的兴奋毒性，从而为治疗这种无法治愈的晚期多发性硬化症开辟了新的见解。