"Many clinicians and researchers are working hard to understand GNE Myopathy and develop an effective therapy. They are our heroes and we hope that they are successful. This section brings to you summaries of the research done by GNE researchers."
GNE Myopathy researcher Dr. Ranjana Arya
School of Biotechnology, Jawaharlal Nehru University, New Delhi-110067, India
Summary of her work:
It is believed that GNE related myopathies are characterized by hyposialylation of glycoproteins in muscle cells of patients and primary defect in either N or O-linked glycosylation. However, it appears from some recent experiments including those from our laboratory that mutant GNE may also affect targets that are not directly related to sialic acid biosynthesis. In particular cytoskeletal network, sarcomere organization and apoptotic signaling are likely to be altered in muscle cells. In absence of clear understanding of the pathomechanism, no treatment is currently available to cure the disease. Our laboratory focuses on deciphering alternate roles of GNE in regulating cell functions with an aim to identify more effective drug targets. We have established a HEK293 cell based assay system where pathologically relevant mutations of GNE are overexpressed alongwith GNE knockdown using shRNA. The system is validated by reduced sialic acid content of the cell and restoration of sialylation after supplementation with 5 mMsialic acid. Using this system, GNE has been shown to affect cell adhesion property via hyposialylation of β-1 integrin. This leads to increased binding of cell to fibronectin and activation of FAK/Src/paxillin to promote focal adhesion assembly. The cytoskeletal network is altered due to misbalance in G-actin and F-actin levels in GNE deficient cell lines. Interestingly, mutation in GNE causes increased apoptosis via mitochondrial dysfunction. The ultrastructure of mitochondria was found to be altered in GNE mutant cells alongwith disruption of membrane potential. Differential levels of ER resident Peroxiredoxin IV were observed in mutant cell lines that do not affect ROS generation but contribute to protein folding. It appears that protein misfolding leads to higher ER retention of mutant proteins as evident by dilation of ER vesicles in GNE mutant cell lines. The role of molecular chaperones in ER stress and protein folding is being deciphered in GNE mutants.Our study clearly provides a base for understanding pathomechanism of GNE myopathy and the opportunity of using cell-based assay for exploring pharmacological drug molecules.