HIF-1α as a Therapeutic Target to Combat Oxidative Stress in Parkinson’s Disease

Abstract

Currently there is an established link that the accumulation of reactive oxidative species (ROS) leads to mitochondrial dysfunction and apoptosis, which is implicated in the formation of Parkinson’s disease (PD). However, there has been a lack of antioxidants that are effective therapeutics for PD patients. In this thesis, HIF-1α, a recently discovered transcription factor, is discussed in its role in a large cellular regulatory system. One of the responses from this system is to combat oxidative stress through the reduction of ROS by upregulating downstream mitochondrial enzymes and microRNA such as LDHA, PDK1, COX4-2, LON, and miR-210. The stabilization of HIF-1α can also activate BNIP3-induced autophagy of the mitochondria (mitophagy), which is important for the clearing of damaged mitochondria. This is crucial as HIF-1α can serve as a potential antioxidant therapeutic target for PD patients. Furthermore, this thesis makes a novel synthesis that given some existing research in cardiac myocytes, it is possible for HIF-1-BNIP3-induced mitophagy to be PINK1 independent, a crucial feature since mutations in the PINK1-Parkin pathway have been shown to cause disrupted mitophagy and contribute to PD pathogenesis. However, future work is necessary to clearly demonstrate that HIF-1-BNIP3-induced-mitophagy is PINK1 independent in dopaminergic neurons while also demonstrating that HIF-PHD inhibitors can effectively rescue dopaminergic neurons in PD models with a compromised PINK1-Parkin pathway.