COMPUTATIONAL ANALYSIS OF POST-TRANSLATIONAL MODIFICATIONS IN MAJOR NEURODEGENERATIVES DISEASES

Abstract

AIM: Post-translational modifications like acetylation and ubiquitination share a common feature that they both act on lysine residue. Acetylation is accountable for transcriptional deregulation which additionally causes mitochondrial dysfunction, autophagic pathway problems, and DNA damage which causes cell death. On the other hand, ubiquitination assists in degrading toxic proteins. Thus, we aim towards the investigation of ubiquitination sites & potential acetylation in SNRPD1 which is responsible for the pathogenesis of AD, PD, ALS, HD, MS, and SCZ. Moreover, we aim towards the identification of impact by these Post- translational modifications on the formational features of SNRPD1 & also the influence upon susceptibility of disease by putative lysine alteration. Lastly, we also focus to identify possible drugs and their impact on SNRPD1 protein. RESULT: 123 DEGs were shortlisted based on the adjusted p-value. PPI network was constructed to analyze the interaction between regulatory proteins in all six diseases. Studying this network gave us HUB genes namely, SNRNP70, SF3B4, and SNRPD1. Critical lysine residues involved were analyzed for SNRNP70, SF3B4, and SNRPD1. Thereafter, protein secondary structure analysis showed SNRPD1 has 9 PTM sites in the helix region while only 1 PTM site in the coiled region. Further, pathway analysis showed that SNRPD1 is involved in the top 13 enriched pathways, whereas, SNRNP70 and SF3B4 are involved in 4 and 5 enriched pathways respectively. Mutation of lysine residues with arginine and aspartic acid indicated that all sites have an effect on disease susceptibility, however, some showed a high confidence score. Lastly, it was found that Artemether is the best drug for SNRPD1 the putative binding site where the CB Dock tool shows that Q24, K44, H26, T16, V15, T14, I69, L70, P71, D72, S97, I96, Y95, and R94. CONCLUSION: The results show that more than the gain of function, there is depletion of ubiquitination function due to loss of acetylated hotspots.