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

该RO 1的前提是测试R21衍生的假设，即线粒体的不适当侵入 锚定蛋白Syntaphilin（SNPH）进入神经元树突在进行性多发性硬化中是有害的 （MS）。进展性MS是指MS的晚期，目前该疾病阶段没有治疗方法。 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树突并在啮齿动物模型中引起兴奋性毒性（Shiverer） 对于进行性MS（Joshi等人，2019，Cell Reports，10月15日出版的文章）。这一发现表明 靶向SNPH阻断树突侵入是治疗进展性MS的一种新方法。 RO 1，我们将解决我们的R21发现提出的三个重要问题，这些问题与基本的 在目标#1中，我们将测试树突状SNPH的病理学 灰质中的侵入与白色物质的病理分离。我们将通过以下方式检验这一假设： 显示在Shiverer模型中治愈白色物质病理（通过遗传抑制轴突生长） 变性和通过髓鞘再生治疗）将不能防止树突状SNPH侵入的病理学。在Aim中 #2，我们将测试树突状SNPH入侵通过偏置激活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 当突触活动释放的谷氨酸溢出到突触外区域时， 通过功能失调的谷氨酸摄取，构成了一个早期的谷氨酸信号级联，触发树突状细胞 SNPH入侵。 结论- SNPH是控制线粒体运动的关键蛋白，对线粒体运动有多方面的影响。 健康和疾病中的神经元行为。自2000年SNPH基因被克隆以来， 都只存在于轴突中该RO的新奇1是一种范式转变，开创了SNPH的研究， 树突翻译意义是令人惊讶的发现，树突状SNPH介导 兴奋性毒性在进展性MS，从而开辟了新的见解，以治疗MS在这个无法治愈的晚期阶段。

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.