SVIP and CMT1A

描述（由申请人提供）：PMP 22主要在髓鞘形成的许旺细胞中表达。PMP22是导致Charcot-Marie-Tooth病（CMT）的最高度流行形式的罪魁祸首基因，其中PMP22的过表达引起CMT1A，PMP22的缺失引起具有压力麻痹倾向的遗传性神经病（HNPP）和Trembler-J（TrJ）点突变引起CMT1E。这些疾病表明必须严格控制PMP 22水平以维持周围神经的健康。我们已经确定了一种新的髓鞘蛋白，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，这是一种高度保守的ATP酶，广泛分布。VCP形成六聚体功能单元，其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种不同辅因子的相互作用来实现的。SVIP就是其中之一。我们的初步数据显示SVIP在髓鞘形成的神经胶质细胞和神经元中高度表达，但在其他组织中很少或不表达。SVIP似乎在蛋白酶体/自噬降解中是重要的。此外，我们的初步研究表明，Pmp22中的毒性功能获得性突变显著抑制了施万细胞中SVIP的表达，这将阻断自噬并损害蛋白质降解。这一发现与PMP 22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SVIP在体内的无效功能是否足以 导致髓鞘中异常的蛋白质聚集。这将使用Svip的组成型和条件性敲除小鼠进行测试。目标二。验证突变型PMP 22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。在这个目标中，我们将敲除Svip或过表达Svip，以确定SVIP如何影响突变体雪旺细胞中的PMP 22降解。总的来说，这项研究预计将产生一系列目前文献中不存在的重要发现。首先，通过研究Svip基因敲除和Pmp 22转基因小鼠，将加深我们对SVIP如何调节体内髓鞘蛋白降解的理解。第二，结果应该建立一个致病性的信号通路，负责异常蛋白质聚集在突变的雪旺细胞。最后，从这项研究中获得的知识应该在其他异常蛋白质聚集的神经退行性疾病中具有广泛的意义。

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.