GNE myopathy – Why is only muscle affected?

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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.