Studies on neurodegeneration and failures of steroidogenesis in triple A syndrome and further investigation of genetic heterogeneity of the disease

AAA综合征是一种罕见的常染色体隐性遗传病，以肾上腺功能不全、软化和失弛缓症为主要症状。在所有病例中，60%的病例与中枢、外周和自主神经系统的进行性功能障碍有关。经典的AAA综合征是由编码核孔蛋白阿拉丁的AAAS基因突变引起的。先前的工作表明，氧化应激参与了该病的发病机制。然而，Aladin突变导致肾上腺功能不全并伴有类固醇合成障碍和神经元退化的确切细胞机制尚不清楚。这些研究是不可能的，因为缺乏适当的人类细胞系统来反映患者的肾上腺皮质和神经元的情况。我们的项目专注于从患者细胞产生IPSCs，以及这些细胞在受影响的组织(运动神经元、肾上腺细胞)中的分化。目的：探讨AAA综合征神经退行性变和类固醇合成失败的机制。此外，对AAA样病患者TRAPPC11突变的功能分析将揭示内质网和高尔基体之间膜转运的障碍，有助于我们理解TRAPPC11在细胞内囊泡运输中的作用。随着对AAA综合征遗传异质性的进一步澄清，我们期望确定导致相似表型的细胞过程中的联系。我们假设相似的表型可能是由相互连接的细胞通路的个别蛋白质的突变引起的。随着这些蛋白质的鉴定和表征，我们可以预见到对这些细胞通路之间的联系的新的见解。这将为AAA综合征的新疗法的开发提供先决条件。

The triple A syndrome is a rare autosomal recessive disorder characterized by the three main symptoms adrenal insufficiency, alacrima and achalasia. In 60% of all cases the disorder is associated with progressive dysfunction of the central, peripheral and autonomic nervous systems. Classical triple A syndrome is caused by mutations in the AAAS gene encodes the nucleoporin ALADIN. Previous work has shown that there is an involvement of oxidative stress in the pathogenesis of the disease. However, the exact cellular mechanisms leading from ALADIN mutations to adrenal insufficiency with impairment of steroidogenesis and degeneration of neurons are not well understood. These investigations were impossible due to the lack of appropriate human cell systems reflecting the situation in adrenal cortex and neurons of patients. Our project focuses on the generation of iPSCs from patient cells and the differentiation of these cells in affected tissues (motor neurons, adrenal cells). The aim is to investigate the mechanisms of neurodegeneration and failure of steroidogenesis in triple A syndrome. In addition, the functional analysis of the TRAPPC11 mutation in patients with a triple A-like disease will uncover disturbances in membrane transport between ER and Golgi and will contribute to our understanding of the role of TRAPPC11 in intracellular vesicle trafficking. With further clarification of genetic heterogeneity of triple A syndrome, we expect to identify links in cellular processes leading to similar phenotypes. We hypothesize that similar phenotypes may be caused by mutations in individual proteins of interconnected cellular pathways. With the identification and characterization of these proteins we envisage new insights into the links between these cellular pathways. This will provide a prerequisite for the development of new therapies for triple A syndrome.