The Protein-Protein Interaction Network of Hereditary Parkinsonism Genes Is a Hierarchical Scale-Free Network

Abstract

Purpose: Hereditary parkinsonism genes consist of causative genes of familial Parkinson’s disease (PD) with a locus symbol prefix (PARK genes) and hereditary atypical parkinsonian disorders that present atypical features and limited responsiveness to levodopa (non-PARK genes). Although studies have shown that hereditary parkinsonism genes are related to idiopathic PD at the phenotyp-ic, gene expression, and genomic levels, no study has systematically investigated connectivity among the proteins encoded by these genes at the protein-protein interaction (PPI) level. Materials and Methods: Topological measurements and physical interaction enrichment were performed to assess PPI networks constructed using some or all the proteins encoded by hereditary parkinsonism genes (n=96), which were curated using the Online Mendelian Inheritance in Man database and literature. Results: Non-PARK and PARK genes were involved in common functional modules related to autophagy, mitochondrial or lyso-somal organization, catecholamine metabolic process, chemical synapse transmission, response to oxidative stress, neuronal apoptosis, regulation of cellular protein catabolic process, and vesicle-mediated transport in synapse. The hereditary parkinson-ism proteins formed a single large network comprising 51 nodes, 83 edges, and three PPI pairs. The probability of degree distribution followed a power-law scaling behavior, with a degree exponent of 1.24 and a correlation coefficient of 0.92. LRRK2 was identified as a hub gene with the highest degree of betweenness centrality; its physical interaction enrichment score was 1.28, which was highly significant. Conclusion: Both PARK and non-PARK genes show high connectivity at the PPI and biological functional levels.