Network Analysis of Neurodegenerative Diseases : A System based Approach to Uncover Perturbed Networks

Background

Over 90,000 coding non-synonymous SNPs (single nucleotide polymorphisms) have been identified in the human genome to date. SNPs directly or indirectly alter protein function, signalling cascade and thus contribute to variation in disease susceptibility, drug efficacy, and drug toxicity. With the accumulation of high throughput datasets, understanding the interaction and crosstalk between pathways is important for understanding pathogenesis of complex diseases from the viewpoints of genetic factor and network context. The underlying mechanisms by which theses complications arise and manifest together remain poorly understood. Applying systems knowledge to identify key nodes in the disease-perturbed networks may provide insights into disease mechanism and effective drug targets.

Results

To understand the exact mechanism underlying disease we performed network-based systems biology approach. We selected a list of SNP associated candidate genes involved in neurodegenerative diseases (NDDs) like Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Parkinson's Disease and Multiple Sclerosis, further clustered it in modules of pathways,  we conducted pathway crosstalk analysis to determine the enriched pathways. We further extended our work to construct disease specific network to uncover perturbed routes in pathways and find out the critical nodes. We examined that NDDs are complex disease and caused by dysregulation of multiple pathways including lipid metabolism, oxidative stress, cellular signalling, growth factor survival pathway, synaptic transmission. Finally we applied network/pathway approach to identify novel candidate genes, some of which could be verified by experiments.

Conclusions

Our study provides disease specific network/pathway analysis approach to determine dysfunctional crosstalk of pathways. Our preliminary results provide the first comprehensive review of the network and pathway characteristics of SNP associated with NDDs candidate genes. We suggest that a gene network based approach is likely to be a valuable tool to elucidate mechanisms underlying common diseases and may identify therapeutic targets.

Keywords: Network analysis, Single nucleotide polymorphism (SNP), Neurodegenerative diseases (NDDs), Systems approach.