Abstract:
The present study sought to investigate the role of Na+/K+-ATPase in disturbed redox homeostasis associated with neuronal cells survival and Parkinson’s disease (PD) pathogenesis in in vitro and in vivo models. The proximity and microenvironment of the catalytically relevant thiols of the sodium transporter were investigated in vitro using mitochondria-rich synaptosomal fraction. More so, the influence of Parkinson’s disease-inducing neurotoxins, 6-hydroxydopamine (6-OHDA) and rotenone, on the transporting function of the electrogenic pump were evaluated in vitro and in vivo. Furthermore, the involvement of an emerging cell death-sensitizing protein, TRIpartite Motif-containing 4 (TRIM4), as well as role of Na+/K+-ATPase vis-á-viz mitochondrial and lysosomal functions was investigated in neuronal and glial cell models of 6-OHDA and rotenone-induced PD. The results revealed that the catalytically essential thiols of this electrogenic protein are likely vicinal thiols that can be inactivated via disulphide crosslinking. In addition, these catalytically relevant thiols are possibly located in microenvironments that are largely hydrophobic in nature. Furthermore, 6-hydroxydopamine inactivated the enzyme in vitro by a mechanism not likely dependent on oxidation of the essential thiols. More so, the presence of Fe2+ had an additive effect on 6-OHDA-mediated enzyme inactivation via complex multi-component oxidative stress-based mechanisms. In addition, in vivo models of rotenone-induced Parkinson’s disease showed inhibition of Na+/K+-ATPase in motor-coordinating regions of the brain as well as increased lipid peroxidation and disturbance of thiol homeostasis. These deleterious effects of rotenone on redox parameters and enzyme activity were ameliorated in animals treated with diphenyl diselenide, a synthetic antioxidant compound. Cellular models of Parkinson’s disease showed a role for a mitochondria-interacting protein, TRIM4, in sensitization of neuronal and glial cells to oxidative stress-mediated cell death by its colocalization with the mitochondria.
Furthermore, it was observed that the inhibition of Na+/K+-ATPase promoted the colocalization of TRIM4 to the mitochondria, and modulated the ubiquitination and autophagy process, culminating in death of neuronal and glial cells. These findings highlight the ubiquitous function of the Na+/K+-ATPase in PD molecular pathways, thus making it a promising candidate as biomarker and therapeutic target in Parkinson’s disease management
