SVIP and CMT1A

SVIP 和 CMT1A

• 批准号: 8426333
• 负责人: JUN LI
• 金额: $ 19.28万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8426333
• 关键词: ATP phosphohydrolase; Affect; Autophagocytosis; Cell Line; Cell physiology; Charcot-Marie-Tooth Disease; Data; Disease; Endoplasmic Reticulum; Genes; Inherited; Knock-out; Knockout Mice; Knowledge; Literature; Mutation; Myelin; Myelin Proteins; Neurodegenerative Disorders; Neuroglia; Neurons; Neuropathy; Paralysed; Pathogenesis; Peripheral Nerves; Peripheral Nervous System Diseases; Play; Point Mutation; Process; Proteins; Role; Schwann Cells; Series; Signal Pathway; Starvation; Testing; Tissues; Transgenic Mice; Up-Regulation; cofactor; gain of function mutation; hereditary neuropathy; in vivo; mouse model; mutant; new therapeutic target; novel; pressure; protein aggregate; protein aggregation; protein degradation; protein expression; valosin-containing protein

DESCRIPTION (provided by applicant): PMP22 is primarily expressed in myelinating Schwann cells. PMP22 is the culprit gene responsible for the most highly prevalent forms of Charcot-Marie-Tooth disease (CMT) with over-expression of PMP22 causing CMT1A, deletion of PMP22 causing hereditary neuropathy with liability to pressure palsies (HNPP) and Trembler-J (TrJ) point mutation causing CMT1E. These diseases suggest that PMP22 level has to be tightly controlled to maintain the wellbeing of the peripheral nerve. We have identified a novel myelin protein, Small Valosin Interacting Protein (SVIP). SVIP interacts with Valosin-Containing Protein (VCP; also called p97), a highly conserved ATPase that is ubiquitously distributed. VCP forms a hexameric functional unit that plays important roles in a variety of cellular functions, including endoplasmic reticulum-associated degradation (ERAD) and autophagy. These highly diversified functions are achieved through VCP interactions with over 27 different cofactors. SVIP is one of them. Our preliminary data show that SVIP is highly expressed in myelinating glia and neurons but is minimal or absent in other tissues. SVIP appears to be important in proteasomal/autophagic degradation. Moreover, our preliminary study has shown that the toxic gain-of-function mutation in Pmp22 drastically suppresses the expression of SVIP in Schwann cells, which would block autophagy and impair the protein degradation. This finding is highly relevant to the pathogenesis in the PMP22-related diseases. Toward this end, we propose the following specific aims: Aim 1.To determine whether null function of SVIP in vivo is sufficient to cause abnormal protein aggregation in myelin. This will be tested using constitutive and conditional knockout mice of Svip. Aim 2. To test the hypothesis that mutant PMP22 promotes protein aggregation by suppressing SVIP expression that would normally activate autophagy processes in Schwann cells. In this aim, we will knockout Svip or over-express Svip to determine how SVIP affects PMP22 degradation in the mutant Schwann cells. Taken together, this study is expected to yield a series of important findings that do not exist in the current literatures. First, it will deepen our understanding how SVIP regulates protein degradation in myelin in vivo by investigating Svip knockout and Pmp22 transgenic mice. Second, results should establish a pathogenic signaling pathway responsible for abnormal protein aggregation in mutant Schwann cells. Finally, knowledge derived from this study should have broad implications in other neurodegenerative disorders with abnormal protein aggregates. PUBLIC HEALTH RELEVANCE: PMP22-related neuropathies, including CMT1A, are the most common forms of inherited peripheral nerve diseases. Our recent studies have identified a novel signaling pathway that is essential in the protein degradation of PMP22. This project will use several mouse models to investigate how this signaling pathway regulates PMP22 degradation, which may yield new therapeutic targets for CMT1A.

描述（由申请人提供）：PMP22主要在髓鞘雪旺细胞中表达。 PMP22 是导致最流行形式的腓骨肌萎缩症 (CMT) 的罪魁祸首基因，PMP22 过度表达会导致 CMT1A，PMP22 缺失会导致遗传性神经病，导致压力性麻痹 (HNPP) 和 Trembler-J。 TrJ)点突变导致CMT1E。这些疾病表明必须严格控制 PMP22 水平才能维持周围神经的健康。我们发现了一种新的髓磷脂蛋白，小缬洛辛相互作用蛋白（SVIP）。 SVIP 与含 Valosin 蛋白 (VCP；也称为 p97) 相互作用，VCP 是一种广泛分布的高度保守的 ATP 酶。 VCP 形成六聚体功能单元，在多种细胞功能中发挥重要作用，包括内质网相关降解 (ERAD) 和自噬。这些高度多样化的功能是通过 VCP 与超过 27 种不同的辅因子相互作用来实现的。 SVIP就是其中之一。我们的初步数据表明，SVIP 在髓鞘神经胶质和神经元中高度表达，但在其他组织中表达很少或不存在。 SVIP 似乎在蛋白酶体/自噬降解中很重要。此外，我们的初步研究表明，Pmp22 中的毒性功能获得性突变会极大地抑制雪旺细胞中 SVIP 的表达，从而阻止自噬并损害蛋白质降解。这一发现与 PMP22 相关疾病的发病机制高度相关。为此，我们提出以下具体目标： 目标 1.确定体内 SVIP 的无效功能是否足以 导致髓磷脂中蛋白质异常聚集。这将使用 Svip 的组成型和条件性敲除小鼠进行测试。目标 2. 检验突变 PMP22 通过抑制 SVIP 表达促进蛋白质聚集的假设，SVIP 表达通常会激活雪旺细胞中的自噬过程。为此，我们将敲除 Svip 或过表达 Svip，以确定 SVIP 如何影响突变雪旺细胞中的 PMP22 降解。总而言之，这项研究预计将产生一系列当前文献中不存在的重要发现。首先，通过研究Svip敲除和Pmp22转基因小鼠，将加深我们对SVIP如何调节体内髓鞘质蛋白降解的理解。其次，结果应该建立一条导致突变雪旺细胞中蛋白质异常聚集的致病信号通路。最后，从这项研究中获得的知识应该对其他具有异常蛋白质聚集的神经退行性疾病具有广泛的影响。 公共卫生相关性：PMP22 相关神经病（包括 CMT1A）是遗传性周围神经疾病的最常见形式。我们最近的研究发现了一种新的信号通路，该通路对于 PMP22 的蛋白质降解至关重要。该项目将使用多种小鼠模型来研究该信号通路如何调节 PMP22 降解，这可能会产生 CMT1A 的新治疗靶点。