Jawaharlal Nehru University, New Delhi
Title: : Understanding pathomechanism and cellular models for neuromuscular disorder associated with sialic acid metabolism
Ranjana Arya completed Ph.D. in the field of Life Sciences from Jawaharlal Nehru University at the age of 29 years followed by post doctoral research experience at Harvard Medical School, Boston, USA and University of North Carolina, Chapel Hill, USA. I worked as Senior Research Scientist in pharmaceutical industry, Ranbaxy Research Laboratories, India for more than 3 years. Presently, I am Assistant Professor at School of Biotechnology, Jawaharlal Nehru University (JNU) since 2008. I have published 23 papers in reputed journals and guided 8 PhD research scholars as supervisor. I am also Assistant Director at University Grants Commission, Human Resource Development Centre, JNU, New Delhi.
Biological basis of pathogenesis of a large number of genetic disorders is not known, particularly for those diseases which affect the neuromuscular system. UDP-GlcNAc 2-epimerase /ManNAc kinase (GNE) is a bifunctional enzyme (N-terminal epimerase and C-terminal Kinase domain) that catalyzes rate limiting step in sialic acid biosynthesis. Homozygous misssense mutations in either epimerase or kinase domain of GNE leads to slowly progressive autosomal recessive genetic neuromuscular disorder, GNE Myopathy. These 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 and altering G-actin and F-actin levels in GNE deficient cell lines. Mutation in GNE caused increased apoptosis via mitochondrial dysfunction that could be rescued by treatment with Insulin-like Growth Factor1 (IGF-1). Differential levels of ER resident Peroxiredoxin IV and upregulation of chaperones generate ER stress in absence of functional GNE. Thus drug molecules regulating chaperone function can modulate protein misfolding and prevent protein aggregation observed in GNE myopathy. Our study clearly provides a base for understanding pathomechanism of GNE myopathy and the opportunity of using cell-based assays for diagnostics as well as exploring pharmacological drug molecules.