This review focuses on the cellular and molecular aspects underlying familial neurohypophyseal diabetes insipidus (DI), a rare disorder that is usually transmitted in an autosomal-dominant fashion. The disease, manifesting in infancy or early childhood and gradually progressing in severity, is caused by fully penetrant heterozygous mutations in the gene encoding prepro-vasopressin-neurophysin II, the precursor of the antidiuretic hormone arginine vasopressin (AVP). Post mortem studies in affected adults have shown cell degeneration in vasopressinergic hypothalamic nuclei. Studies in cells expressing pathogenic mutants and knock-in rodent models have shown that the mutant precursors are folding incompetent and fail to exit the endoplasmic reticulum (ER), as occurs normally with proteins that have entered the regulated secretory pathway. A portion of these mutants is eliminated via ER-associated degradation (ERAD) by proteasomes after retrotranslocation to the cytosol. Another portion forms large disulfide-linked fibrillar aggregates within the ER, in which wild-type precursor is trapped. Aggregation capacity is independently conferred by two domains of the prohormone, namely the AVP moiety and the C-terminal glycopeptide (copeptin). The same domains are also required for packaging into dense-core secretory granules and regulated secretion, suggesting a disturbed balance between the physiological self-aggregation at the trans-Golgi network and avoiding premature aggregate formation at the ER in the disease. The critical role of ERAD in maintaining physiological water balance has been underscored by experiments in mice expressing wild-type AVP but lacking critical components of the ERAD machinery. These animals also develop DI and show amyloid-like aggregates in the ER lumen. Thus, the capacity of the ERAD is exceeded in autosomal dominant DI, which can be viewed as a neurodegenerative disorder associated with the formation of amyloid ER aggregates. While DI symptoms develop prior to detectable cell death in transgenic DI mice, the eventual loss of vasopressinergic neurons is accompanied by autophagy, but the mechanism leading to cell degeneration in autosomal dominant neurohypophyseal DI still remains unknown.

中文翻译：

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蛋白质聚集和降解在常染色体显性遗传性神经下垂性尿崩症中的作用。

这篇综述着重于家族性神经下垂体尿崩症（DI）的细胞和分子方面，这是一种罕见的疾病，通常以常染色体显性方式传播。该疾病表现在婴儿期或儿童早期，并逐渐发展至严重程度，是由抗利尿素精氨酸加压素（AVP）的前体加压素-神经素II前体基因中的完全渗透性杂合突变引起的。在受影响的成年人中进行的验尸研究表明，血管加压素下丘脑核中的细胞变性。在表达致病突变体和敲入啮齿动物模型的细胞中进行的研究表明，突变体前体折叠能力不佳，无法退出内质网（ER），就像进入调节分泌途径的蛋白质通常会发生这种情况一样。这些突变体的一部分在逆向转运至细胞质后通过蛋白酶体通过ER相关降解（ERAD）消除。另一部分在ER内形成大的二硫键连接的原纤维聚集体，其中捕获了野生型前体。聚集能力由激素原的两个结构域独立赋予，即AVP部分和C端糖肽（肽素）。包装成致密核心分泌颗粒和调节分泌也需要相同的结构域，这表明反反的高尔基体网络的生理自聚集与避免疾病中内质网过早形成聚集之间的平衡失衡。在表达野生型AVP但缺乏ERAD机制关键成分的小鼠中进行的实验强调了ERAD在维持生理水平衡中的关键作用。这些动物也发展成DI，并在ER管腔中显示出淀粉样的聚集体。因此，在常染色体显性DI中超过了ERAD的能力，可以将其视为与淀粉样蛋白ER聚集体形成有关的神经退行性疾病。虽然在转基因DI小鼠中可检测到细胞死亡之前会出现DI症状，但血管加压素能神经元的最终丧失会伴随自噬，但是导致常染色体显性神经垂体DI发生细胞变性的机制仍然未知。在常染色体显性DI中超过了ERAD的能力，这可被视为与淀粉样蛋白ER聚集体形成有关的神经退行性疾病。虽然在转基因DI小鼠中可检测到细胞死亡之前会出现DI症状，但血管加压素能神经元的最终丧失会伴随自噬，但是导致常染色体显性神经垂体DI发生细胞变性的机制仍然未知。在常染色体显性DI中超过了ERAD的能力，这可被视为与淀粉样蛋白ER聚集体形成有关的神经退行性疾病。虽然在转基因DI小鼠中可检测到细胞死亡之前会出现DI症状，但血管加压素能神经元的最终丧失会伴随自噬，但是导致常染色体显性神经垂体DI发生细胞变性的机制仍然未知。