Computational Analysis Indicates That PARP1 Acts as a Histone Deacetylases Interactor Sharing Common Lysine Residues for Acetylation, Ubiquitination, and SUMOylation in Alzheimer's and Parkinson's Disease

Abstract

Aim/Hypothesis: Lysine residues are known for the post-translational modifications (PTMs) such as acetylation, ubiquitination, and SUMOylation. In acetylation, histone deacetylase (HDAC) and its interactors cause transcriptional deregulation and cause mitochondrial dysfunction, apoptosis, inflammatory response, and cell-cycle impairment that cause brain homeostasis and neuronal cell death. Other regulatory PTMs involved in the pathogenesis of neurodegenerative diseases (NDDs) are ubiquitination and SUMOylation for the degradation of the misfolded proteins. Thus, we aim to investigate the potential acetylation/ubiquitination/SUMOylation crosstalk sites in the HDAC interactors, which cause NDDs. Furthermore, we aim to identify the influence of PTMs on the structural features of proteins and the impact of putative lysine mutation on disease susceptibility. Last, we aim to examine the impact of the putative mutation on acetylated lysine for ubiquitination and SUMOylation. Results: Herein, we integrate 1455 genes, 3094 genes, and 1940 genes related to HDAC interactors, Alzheimer's disease (AD), and Parkinson's disease (PD), respectively. Furthermore, the protein-protein interaction and PTM integrations from different databases identified 32 proteins that are associated with HDAC, AD, and PD with 1489 potential lysine-modified sites. HDAC interactors poly(ADP-ribose) polymerase 1 (PARP1), nucleophosmin (NPM1), and cyclin-dependent kinase 1 (CDK1) involved in the progression of NDDs and 64 and 75% of PTM sites in PARP1, NPM1, and CDK1 fall into coiled and ordered regions, respectively. Moreover, 15 putative lysine sites have been found in the crosstalk and K148, K249, K528, K637, K700, and K796 of PARP1 are crosstalk hotspots. Conclusion: The loss of acetylated hotspot sites results in the loss of ubiquitination and SUMOylation function on nearby sites, which is relatively higher when compared to the gain of function.