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

• 批准号: 10219369
• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10219369
• 关键词: Address; Affect; Agonist; Animal Model; Axon; Basic Science; Behavior; Cells; Cerebellum; Cessation of life; Clinical; Cloning; Coupled; Coupling; Demyelinations; Dendrites; Disease; Disease model; Fiber; Functional disorder; Genetic; Glutamate Receptor; Glutamate Transporter; Glutamates; Health; Immobilization; Injections; Kinesin; Mediating; Methods; Mitochondria; Mitochondrial Proteins; Modeling; Movement; Multiple Sclerosis; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nerve Degeneration; Neurologic; Neurons; Nuclear; Pathologic; Pathology; Pathway interactions; Phase; Proteins; Purkinje Cells; Receptor Activation; Reporting; Rodent Model; Secondary to; Shivering; Signal Transduction; Surface; Synapses; Testing; Therapeutic; Toxic effect; axonal degeneration; design; disability; dysmyelination; excitotoxicity; follow-up; glutamatergic signaling; gray matter; insight; migration; novel; oligodendrocyte precursor; precursor cell; preemptive intervention; preservation; prevent; receptor; recruit; remyelination; syntaphilin; treatment strategy; uptake; white matter; young adult

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.

这种RO1的前提是检验R21派生的假设，即线粒体的不适当侵入 在进行性多发性硬化症中锚定蛋白合成酶(SNPH)进入神经元树突是有害的 (毫秒)。进展性多发性硬化症是指多发性硬化症的晚期，目前该疾病阶段尚无治疗方法。 SNPH通常只在轴突中表达。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) 对于进展型多发性硬化症(Joshi等人，2019，Cell Reports，10月15日出版的文章)。这一发现表明 靶向SNPH阻止树突侵入是本次随访中对进展性MS的一种新的治疗方法。 RO1，我们将解决R21发现提出的三个重要问题，这些问题与基本 MS的科学和临床方面在目标1中，我们将测试树突状SNPH的病理学假设 灰质的侵入与白质的病理是分离的。我们将通过以下方式验证这一假设 表明治疗寒战模型中的白质病理(通过遗传抑制轴突 并不能阻止树突状SNPH侵袭的病理改变。在AIM #2，我们将测试树突状SNPH入侵通过偏向激活SNPH导致兴奋性毒性的假设 NMDA受体朝向促死亡、突触外的NMDA受体。在目标3中，我们将检验这一假设 当谷氨酸溢出到突触外区域时，突触活动释放的谷氨酸加剧 通过功能障碍的谷氨酸摄取，构成早期谷氨酸信号级联反应，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基因克隆以来，SNPH在神经元中的研究 一直只存在于轴突中。这个RO1的新颖性是一个范式的转变，开创了SNPH研究的先河 树枝状结构。翻译的意义是树突SNPH介导的令人惊讶的发现 进展性多发性硬化症的兴奋性毒性，从而为治疗这一无法治愈的晚期多发性硬化症开辟了新的见解。