GNE myopathy – Why is only muscle affected?

GNE肌病是由唾液酸途径中的第一种酶功能障碍引起的遗传性疾病。唾液酸是终止蛋白质和脂质糖基化的关键糖，因此对细胞相互作用至关重要。唾液酸途径的中断与常见疾病如癌症和导致神经表型的遗传缺陷有关。由于唾液酸的合成是普遍存在的，为什么在GNE肌病中只有肌肉受到影响仍然没有解决。为了解决这个问题，我将联合收割机结合我在人类诱导多能干细胞（hiPSC）方面的专业知识和宿主组最近对唾液酸途径中间产物N-乙酰甘露糖胺（ManNAc）的关键作用的发现。本研究的主要目的是通过以下三个方面来研究GNE肌病的特异性肌肉表型的分子原因和ManNAc代谢的特殊性：1）GNE肌病患者hiPSC衍生的心脏和骨骼肌模型的建立和功能表征; 2）GNE缺乏的心脏和骨骼肌模型的糖蛋白组学和代谢组学分析，以及3）GNE缺乏的生化和功能后果的代谢修复。通过这项研究，我希望阐明ManNAc及其耻骨肌特异性代谢的作用，这将有助于GNE肌病的诊断和治疗干预。通过寻找唾液酸产生的组织特异性机制的解释，我的目标是进一步确定新的目标，以纠正其他疾病中中断的唾液酸代谢。

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.