Probing the Role of Calcium Signaling in Huntington’s Disease (HD)

Abstract

Huntington’s disease (HD) is a neurodegenerative disorder, caused by the expansion of CAG repeats in the Huntingtin gene. Many recent studies have suggested that calcium dyshomeostasis is a one of the major causative factors in HD pathogenesis. It have been advocated that Mutant Huntingtin (mHTT) affects calcium signaling by sensitizing Inositol 1,4,5 triphosphate receptors (IP3R) to activation by Inositol 1,4,5 triphosphate (IP3). Additionally, Polyglutamine expansion in HTT leads to neuronal death of Medium Spiny Neurons (MSNs) in the striatum due to sensitization of IP3R. Although the genetic cause of the disease has been known for a long time, no effective therapeutic strategy has been developed so far due to complexity of the disease mechanistic and regulation. In this research, we constructed a Biological Regulatory Network (BRN) and performed calcium dyshomeostasis target validation of Huntingtin protein. Subsequently, molecular docking and molecular dynamics simulations were performed to develop potential therapeutic interventions against the identified drug targets for Huntington’s disease. The Molecular Docking studies are employed on HTT protein with PDB ID 6X9O with binding site residues Asp2737, Glu2738, Asp2758, Lys2759, Glu3106, Glu3107, and Leu3108. Four potential ligands namely, Gabapentin, Mannitol, Paroxetine and an undefined ligand, were selected from the curated dataset of sixty-nine inhibitors, for further MD Simulations. The average RMSD values for these complexes are 0.58, 0.28, 0.29 and 0.29 respectively while the average RMSF values are 0.25, 0.43, 0.25 and 0.27 respectively. These findings revealed that these complexes maintained stable conformations with high flexibility at functional sites that suggests the potential therapeutic efficacy in modulation of the pathological aspects of HD. Among these four ligand complexes, the inhibitor Mannitol showed the highest RMSD value indicating the highest stability compared to the others. Our study was able to validate HTT as potential drug target and comprehend the xvi | P a g e molecular mechanism of the disease which can assist in developing novel therapeutic strategies for the treatment of HD.