Pathogenesis of Myelin Protein Zero Neuropathies in Transgenic Mice

转基因小鼠髓磷脂蛋白零神经病的发病机制

• 批准号: 7087631
• 负责人: Lawrence Wrabetz
• 金额: $ 24.3万
• 依托单位: ISTITUTO SCIENTIFICO SAN RAFFAELE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7087631
• 关键词: Schwann cells; gene mutation; genetically modified animals; human; intracellular; laboratory mouse; lipids; model; mutant; myelin; myelinopathy; nerve /myelin protein; phenotype; proteasome; proteins; transcription factor

DESCRIPTION (provided by applicant): We propose to identify the intracellular pathogenesis of Myelin Protein Zero (MPZ)-related neuropathies. We have created a unique set of transgenic mice expressing various human mutations of Mpz that provide proof of principle that gain of abnormal function, deriving from diverse intracellular locations, can cause variable myelinopathy phenotypes. In one model, POS63del, we have identified the unfolded protein response (UPR). Our hypothesis is that mutant proteins that elicit myelinopathies from intracellular locations away from myelin, produce more severe neuropathy because they more generally perturb Schwann cells (kill them by apoptosis) or the program of myelin protein and lipid synthesis. Here we will exploit our models, and in particular POS63del mice, to understand how intracellular retention of mutant proteins produces demyelination. We will fully evaluate the UPR downstream mediators in POS63del nerves, and explore how the S63 alteration produces an unfolded protein. We will genetically eliminate the unfolded protein response mediator, CHOP, and characterize the effect on neuropathy to show that the UPR causes demyelinating neuropathy. We will systematically identify target genes of the CHOP transcription factor in diseased nerve, in order to test our hypothesis that the 'toxic' effect is on pivotal regulators, or multiple members of the program of myelin protein and lipid synthesis. Finally, we will explore in a novel proteasome indicator mouse whether the UPR induces inefficient proteasome function and thereby alters the physiological degradation of proteins such as PMP22, thereby inducing a PMP22 overexpression neuropathy. Charcot Marie Tooth hereditary neuropathies affect 150,000 people in the US and 3,000,000 people worldwide and account for significant lifelong disability and important economic loss. About one quarter of these neuropathies result from mutations that permit the expression of 'toxic1 proteins that interfere with the capacity of Schwann cells to form and maintain myelin in nerves. Little is known about the mechanisms of toxicity. This study will identify some of these mechanisms, and inform potential therapeutic strategies for hereditary neuropathies. The same mechanisms and strategies may also be relevant to the broad category of diseases associated with misfolded proteins including Alzheimer disease and Diabetes.

描述（由申请人提供）：我们提出鉴定髓磷脂蛋白零（MPZ）相关神经病变的细胞内发病机制。我们已经创建了一组独特的转基因小鼠，表达各种人类Mpz突变，提供了来自不同细胞内位置的异常功能的获得可以引起可变髓鞘病表型的原理证明。在一个模型中，POS63del，我们已经确定了未折叠蛋白质反应（UPR）。我们的假设是，从远离髓鞘的细胞内位置引起髓鞘病变的突变蛋白质，产生更严重的神经病变，因为它们更普遍地扰乱许旺细胞（通过凋亡杀死它们）或髓鞘蛋白和脂质合成的程序。在这里，我们将利用我们的模型，特别是POS 63 del小鼠，来了解突变蛋白的细胞内保留如何产生脱髓鞘。我们将全面评估POS63del神经中的UPR下游介质，并探索S63改变如何产生未折叠蛋白。我们将从遗传学上消除未折叠蛋白反应介质CHOP，并描述其对神经病变的影响，以表明UPR导致脱髓鞘神经病变。我们将系统地确定靶基因的CHOP转录因子在患病的神经，以测试我们的假设，即“毒性”的影响是对关键的监管机构，或多个成员的程序髓鞘蛋白和脂质的合成。最后，我们将在一种新的蛋白酶体指示小鼠中探索UPR是否诱导低效的蛋白酶体功能，从而改变蛋白质如PMP 22的生理降解，从而诱导PMP 22过表达神经病变。Charcot玛丽牙遗传性神经病在美国影响150，000人，在全世界影响3，000，000人，并造成重大的终身残疾和重大的经济损失。大约四分之一的神经病变是由突变引起的，这些突变允许毒性蛋白的表达，干扰许旺细胞在神经中形成和维持髓鞘的能力。对毒性机制知之甚少。这项研究将确定其中的一些机制，并为遗传性神经病提供潜在的治疗策略。同样的机制和策略也可能与包括阿尔茨海默病和糖尿病在内的与错误折叠蛋白质相关的广泛疾病类别有关。