How do dominant PMP2 mutations cause demyelinating neuropathy?

周围神经病变是美国最常见的神经退行性疾病之一， 总患病率为1.66%，60岁以上人群患病率为6.6%。尽管它的流行， 在相当一部分患者中无法确定病因，除非有可治疗的病因， 一旦确诊，治疗仅限于症状。这些发人深省的统计数字已经笼罩在这个领域， 几十年然而，如果一个人接受这样的观点，即神经病的遗传原因（这是正在发生的）， 以惊人的速度发现）将可能是信息丰富的，然后利用这个丰富的信息源 应该提供解开病因的钥匙，从而找到神经病的新治疗方法， 不仅是特定的遗传原因，还有更常见的原因所涉及的途径， 例如糖尿病性神经病。从这个角度来看，CMT的每一个新原因都有助于完成 分子缺陷是如何导致神经病变的，还有许多意想不到的惊喜。 我们最近描述了一种新的显性遗传性脱髓鞘神经病的遗传原因， 人类-新生，PMP 2的显性突变。PMP 2编码髓磷脂蛋白P2，其是一种 与脂肪酸和胆固醇结合的胞质蛋白质。是致密髓鞘的次要成分; 在PNS髓磷脂中比在CNS髓磷脂中更丰富。描述的疾病相关突变 到目前为止，p.Ile43Asn、p.Thr51Pro和p.Ile52Thr在蛋白质的类似区域中被发现， 这就产生了这样一种想法，即突变体在髓鞘形成的许旺细胞中具有共同的毒性功能增益 导致脱髓鞘我们使用CRISPR-Cas9在小鼠中制造了一个突变，p.Ile52Thr， 并建议在以下具体目标中分析该小鼠模型。 目的1：p.Ile52Thr突变小鼠是否发生脱髓鞘性神经病变？ 我们产生了四个独立的小鼠品系，它们携带p.Ile52Thr突变， 在这三条线路上传输。我们将进行病理和电生理分析 在三个品系的每一个上，比较纯合的（p.Ile52Thr/p.Ile52Thr）、杂合的（p.Ile52Thr/p.Ile52Thr）、 （p.Ile52Thr/+）和野生型（WT）（+/+）小鼠。虽然杂合子小鼠更准确地建模 对于人类疾病，我们包括纯合子小鼠，因为它们可能具有更明显的 表型 目标二。PNS髓鞘在p.Ile52Thr突变小鼠中改变了吗？ 由于P2与脂肪酸和胆固醇结合，我们将研究p.Ile43Asn 突变改变了髓鞘的脂质组成，通过脂质组学分析神经， 电子显微镜下致密髓鞘。

Peripheral neuropathy is one of the most common neurodegenerative diseases in America, with an overall prevalence of 1.66%, and 6.6% in persons older than 60 years. In spite of its prevalence, a cause cannot be identified in a substantial fraction of patients, and unless a treatable cause is identified, treatment is limited to symptoms. These sobering statistics have hung over the field for decades. However, if one accepts the idea that the genetic causes of neuropathy (which are being found at an astounding rate) will likely be informative, then exploiting this rich source of information should provide the keys to unlocking the causes and thus finding new treatments of neuropathies, not only the specific genetic causes, but also the pathways involved in the more common cause, such as diabetic neuropathy. In this view, each new cause of CMT helps to complete the “puzzle” of how molecular defects cause neuropathy, with many unanticipated surprises. We recently described a new genetic cause of dominantly inherited demyelinating neuropathy in humans – de novo, dominant mutations in PMP2. PMP2 encodes the myelin protein P2, which is a cytosolic protein that binds to fatty acids and cholesterol. It is minor component of compact myelin; more abundant in the PNS myelin than in CNS myelin. The disease-associated mutations described to date - p.Ile43Asn, p.Thr51Pro, and p.Ile52Thr – are found in a similar region of the protein, giving rise to the idea that the mutants share a common toxic gain of function in myelinating Schwann cells that results in demyelination. We have made one mutation in mice, p.Ile52Thr, using CRISPR-Cas9, and propose to analyze this mouse model in the following specific aims. Aim 1: Do p.Ile52Thr mutant mice develop a demyelinating neuropathy? We generated four, independent lines of mice harboring the p.Ile52Thr mutation, and have germ line transmission in three of these lines. We will perform pathological and electrophysiological analysis on each of the three lines, comparing homozygous (p.Ile52Thr/p.Ile52Thr), heterozygous (p.Ile52Thr/+), and wild type (WT) (+/+) mice. Although heterozygous mice more accurately model the human disease, we included homozygous mice because they might have a more pronounced phenotype. Aim 2. Are PNS myelin sheaths altered in p.Ile52Thr mutant mice? Because P2 binds to fatty acids and cholesterol, we will investigate the possibility that the p.Ile43Asn mutation alters the lipid composition of myelin, by analyzing nerves by lipidomics and by performing electron microscopy of compact myelin.