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(申请人提供)：PMP22主要在髓鞘雪旺细胞中表达。PMP22基因是导致最常见的夏科-玛丽-牙病(CMT)的罪魁祸首，PMP22的过度表达导致CMT1A，PMP22的缺失导致遗传性神经病，易患压力性瘫痪(HNPP)，以及颤抖者-J(TRJ)点突变导致CMT1E。这些疾病表明，必须严格控制PMP22的水平，以维持周围神经的健康。我们已经鉴定出一种新的髓鞘蛋白--小Valosin相互作用蛋白(SVIP)。SVIP与含有Valosin的蛋白(VCP；也称为p97)相互作用，VCP是一种广泛分布的高度保守的ATPase。VCP形成一个六聚体功能单位，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而实现的。SVIP就是其中之一。我们的初步数据显示，SVIP在髓鞘胶质细胞和神经元中高表达，但在其他组织中很少表达或不表达。SVIP似乎在蛋白酶体/自噬降解中起重要作用。此外，我们的初步研究表明，PMP22的毒性功能获得突变显著抑制了雪旺细胞中SVIP的表达，这将阻止自噬并损害蛋白质的降解。这一发现与PMP22相关疾病的发病机制高度相关。为此，我们提出了以下具体目标：目的1.确定体内SVIP的零功能是否足以 导致髓鞘内蛋白质异常聚集。这将用SKIP的结构性和条件性基因敲除小鼠进行测试。目的2.验证突变体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的自噬过程。在这个目标中，我们将敲除Svip或过表达Svip，以确定SVIP如何影响突变的雪旺细胞中PMP22的降解。综上所述，这项研究有望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基因敲除和PMP22转基因小鼠，它将加深我们对SVIP如何调节体内髓鞘中蛋白质降解的理解。其次，结果应该建立一个致病信号通路，负责突变的雪旺细胞中的异常蛋白质聚集。最后，来自这项研究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意义。 公共卫生相关性：与PMP22相关的神经病，包括CMT1A，是最常见的遗传性周围神经疾病。我们最近的研究发现了一个新的信号通路，它在PMP22的蛋白质降解中是必不可少的。这个项目将使用几个小鼠模型来研究这个信号通路如何调节PMP22的降解，这可能会为CMT1A产生新的治疗靶点。