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

• Applicant: Privatdozentin Dr. Katrin Köhler
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 324141114

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.

• DFG Programme: Research Grants