Studying the Effect of Alpha-Synuclein and Parkinson's Disease Linked Mutants on Inter Pathway Connectivities

Parkinson's Disease is a common neurodegenerative disease. The differential expression of alpha-synuclein within Lewy Bodies leads to this disease. Some missense mutations of alpha-synuclein may resultant in functional aberrations. In this study, our objective is to verify the functional adaptation due to early and late-onset mutation which can trigger or control the rate of alpha-synuclein aggregation. In this regard, we have proposed a computational model to study the difference and/or similarities among the Wild type alpha-synuclein and two mutations G51D and E46K which are responsible for slow and fast aggregation respectively. Evolutionary sequence space analysis is also performed in this experiment. Subsequently, a comparative study has been performed between structural information and sequence space outcomes. The study shows the structural variability among the selected subtypes. This information assists inter pathway modeling due to mutational aberrations. Based on the structural variability, we have identified the protein-protein interaction partners for each protein that helps to increase the robustness of the inter-pathway connectivity. As per the inter-pathway networks, drug addiction has clear impacts on both the mutations i.e., G51D-slow, and E46K-fast and can be considered as the reason for early-onset Parkinson’s Disease. Finally, three top pathways associated with drug addiction viz., Amphetamine addiction, alcoholism, and Cocaine addiction show the higher influence in the mutated pathway networks based on the PageRank Algorithm where Dopaminergic Synapse system is also found within the same list in terms of Parkinson’s Disease pathogenicity.