SVIP and CMT1A

描述（由申请人提供）：PMP22主要在髓鞘雪旺细胞中表达。PMP22是最常见的沙科-玛丽-图斯病（CMT）的罪魁祸首基因，PMP22的过度表达导致CMT1A， PMP22的缺失导致遗传性神经病变伴压迫性麻痹（HNPP）和Trembler-J （TrJ）点突变导致CMT1E。这些疾病表明，PMP22水平必须严格控制，以维持周围神经的健康。我们已经鉴定出一种新的髓磷脂蛋白，小Valosin相互作用蛋白（SVIP）。SVIP与Valosin-Containing Protein （VCP，也称为p97）相互作用，VCP是一种高度保守的atp酶，普遍分布。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在髓鞘胶质细胞和神经元中高度表达，但在其他组织中很少或不存在。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的毒性功能获得性突变会显著抑制雪旺细胞中SVIP的表达，从而阻断自噬，损害蛋白降解。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：目标一。确定体内SVIP的零函数是否足以

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.