GNE myopathy – Why is only muscle affected?

GNE肌病是一种遗传性疾病，由唾液酸途径中的第一种酶功能障碍引起。唾液酸是终止蛋白质和脂肪糖基化的关键糖类，因此对细胞相互作用至关重要。唾液酸途径的中断与癌症等常见疾病和导致神经表型的遗传缺陷有关。由于唾液酸的合成无处不在，为什么只有肌肉在GNE肌病中受到影响，这一问题仍未解决。为了解决这个问题，我将把我在人类诱导多能干细胞(HiPSC)方面的专业知识与宿主小组关于唾液酸途径中间产物N-乙酰甘露糖胺(ManNAc)的关键作用的最新发现结合起来。在拟议的项目中，我的目标是通过三个关键目标来研究GNE肌病独有的肌肉表型的分子原因和ManNAc代谢的特殊性：1)从GNE肌病患者的HiPSC来源的心脏和骨骼肌模型的产生和功能特征；2)GNE缺乏的心脏和骨骼肌模型的糖蛋白质组和代谢组学分析；3)GNE缺乏的生化和功能后果的代谢修复。通过这项研究，我期望阐明ManNAc的作用及其可能的肌肉特异性代谢，将有助于GNE肌病的诊断和治疗干预。通过找到唾液酸产生的组织特异性机制的解释，我的进一步目标是确定新的靶点，以纠正其他疾病中断的唾液酸代谢。

GNE myopathy is an inheritable disease caused by a dysfunction of the first enzyme in the sialic acid pathway. Sialic acids are the key sugars that terminate glycosylation of proteins and lipids and are therefore crucial for cellular interactions. Disruptions in the sialic acid pathway have been associated with common diseases such as cancer and with genetic defects causing neurological phenotypes. As sialic acid synthesis is ubiquitous, it remains unsolved why only the muscle is affected in GNE myopathy. To tackle this issue, I will combine my expertise in human induced pluripotent stem cells (hiPSC) with recent findings of the host group on a crucial role of the intermediate product of the sialic acid pathway, N-acetylmannosamine (ManNAc). In the proposed project I aim to investigate the molecular reason for the exclusively muscular phenotype of GNE myopathy and the peculiarity of ManNAc metabolism by addressing three Key Objectives: 1) Generation and functional characterisation of hiPSC-derived heart and skeletal muscle models from patients with GNE myopathy; 2) Glycoproteomic and metabolomic analysis of the GNE deficient heart and skeletal muscle models and 3) Metabolic repair of the biochemical and functional consequences of GNE deficiency .With this study I expect to elucidate the role of ManNAc and its putatively muscle-specific metabolism, which will aid diagnostics and therapeutic intervention in GNE myopathy. By finding an explanation for the tissue-specific mechanisms of sialic acid production, I furthermore aim to identify novel targets to correct disrupted sialic acid metabolism in other diseases.