ACETYLATION MECHANISM AND HDAC ENZYMES IN NEURODEGENERATIVE DISEASES

Abstract

Neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease are characterized by the loss of neuronal cells due to the accumulation of toxic proteins, namely β amyloid, tau, α-synuclein, and others. Studies have demonstrated that several contributing factors, such as aging, mitochondrial dysfunction, DNA damage, misfolded protein aggregation, impaired ubiquitin-proteasome system and autophagy-lysosomal pathway, and environmental toxins involved in the progression and pathogenesis of Alzheimer’s and Parkinson’s disease. However, post-translational modifications play a crucial role in the alteration of misfolded protein aggregates and impaired protein degradation pathways. Post translational modifications are covalently attached modifications that alter the functions of proteins without changing the structure of protein. Additionally, lysine residues are known for the post-translational modifications, namely acetylation, ubiquitination, and SUMOylation. In acetylation, histone deacetylases 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. Another regulatory post translational modification involved in the pathogenesis of neurodegenerative diseases are ubiquitination and SUMOylation for the degradation of the misfolded proteins. Additionally, mounting evidence demonstrated that heavy metals, such as copper, chromium, cobalt, and nickel, increases the β-amyloid and tau aggregation in the pathogenesis of Alzheimer’s and Parkinson’s disease by activating different signaling events. For instance, copper induces the formation of reactive oxygen species to cause mitochondrial dysfunction and DNA damage, whereas, chromium elevates neuroinflammatory response and neuronal apoptosis. Similarly, cobalt increases tau hyperphosphorylation and promotes tau aggregation, whereas, nickel elevates β-amyloid aggregation. Moreover, integration of omics data and deciphering the mechanism of a biological regulatory network could be a promising approach to reveal the molecular mechanism involved in the progression of viii | P a g e complex diseases, including Alzheimer’s and Parkinson’s. Despite having an overlapping mechanism in the etiology of Alzheimer’s and Parkinson’s disease, the exact mechanism and signaling molecules behind them are still unknown. Further, the acetylation mechanism and histone deacetylase enzymes provide a positive direction towards studying shared phenomenon between Alzheimer’s disease and Parkinson’s disease pathogenesis. Herein, we employed an integrative approach to analyze the transcriptomics data that established a potential relationship between Alzheimer’s and Parkinson’s disease. Firstly, we aim to investigate the potential conventional biomarkers and regulatory TFs involved in the pathogenesis of AD and PD simultaneously with the help of microarray datasets and the network-biology approach. The identified proteomics and transcriptomics signatures were further analyzed to investigate the potential lysine residue for acetylation and deacetylation activity, along with the determination of the type of histone deacetylase enzyme being involved in the disease progression. Lately, the study focuses on investigating conserved amino acid residues involved in the lysine acetylation/deacetylation process along with the structural selectivity of molecular signatures, which could be crucial for protein acetylation or deacetylation activity. Further, we aim to investigate the potential acetylation/ubiquitination/SUMOylation crosstalk sites in the histone deacetylase interactors, which causes NDDs. Further, we aim to identify the influence of post translational modifications on structural features of proteins and the impact of lysine mutation on disease susceptibility. Additionally, we aim to examine the impact of the mutation on acetylated lysine for the ubiquitination and SUMOylation. Moreover, we aim to identify the crucial proteins involved in metal toxicity-induced Alzheimer’s disease through network biology, followed by identifying regulatory transcription factors associated with crucial proteins. Further, we aim to determine the critical lysine residue and the role of CREBBP induce acetylation on transcription factors. Lately, we have focused on identifying micro RNAs associated with CREBBP and transcription factors simultaneously. Lastly, we aim to identify ix | P a g e the potential long non-coding RNA, serving as a sponge to micro RNAs. Lastly, we investigate the potential histone deacetylase 10 inhibitor using machine learning approach. Our results highlighted the importance of CREBK292 and HINFPK330 as a potential biomarker in Alzheimer’s and Parkinson’s pathology. Further, we reported the importance of PARP1 as a crucial regulatory molecule in Alzheimer’s disease and Parkinson’s disease. Lately, we demonstrated that the OIP5-AS1/miR-129-5p/CREBBP axis is a potential therapeutic target in metal toxicity-induced Alzheimer’s disease pathogenesis. Lastly, we reported the role of anti-psychotic drugs, namely Zimeldine and Dibenzapine as potential histone deacetylase 10 inhibitors in Alzheimer’s disease therapeutics.