Research Projects

GNE Myopathy (GNEM) is a rare neuromuscular disorder characterized by muscle weakness and difficulty walking in adults aged 20-40. It is caused by mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase GNE/MNK, a key enzyme in the sialic acid biosynthetic pathway. The National Human Genome Research Institute estimates that around 13,000 patients in Asia suffer from GNEM. The pathophysiology of the disease progression is still disputed, with some believed mechanisms including hyposialylation of glycoproteins due to reduced GNE enzyme activity. However, alternative mechanisms have been suggested, such as reduced interaction of GNE with α-actinins, alteration in Endoplasmic Reticulum ER redox state due to downregulation of peroxiredoxin IV in GNE mutant cells, and misfolding of proteins. A recent study found that downregulation of Heat Shock Protein 70 (HSP70) in GNE mutant cells is potentially responsible for protein aggregation in GNEM. However, experts believe that supplementation is unlikely to work as only modest hyposialylation is observed in patients with GNEM. Neurodegenerative diseases have similarities to GNEM, with β-amyloid deposition and protein aggregation due to impaired chaperone function. Drugs that amplify the heat shock response have shown clinically meaningful effects to treat neurodegenerative diseases. The present study aims to investigate HSP70 agonists for enhancing GNE activity and providing treatment options for GNEM.