Hypoxia Signaling in Parkinson’s Disease: There Is Use in Asking “What HIF?”

SIMPLE SUMMARY: Parkinson’s disease is a neurodegenerative disorder characterized by the death of a specific subset of dopamine-producing neurons. This triggers problems with movement as dopamine is key in regulating motor control. To date, available treatments compensate for dopamine deficiency but are not able to reverse the progressive neuronal cell damage. The exact cause of the loss of these neurons remains to be determined, although it has been linked to environmental factors, genetic predisposition and modifications to vital molecular pathways. Recent evidence shows that events causing reductions in oxygen supply (hypoxia) to these neurons might also be related to PD development. This review explores the link between hypoxia and Parkinson’s disease as well as promising new therapeutic strategies based on HIF-1α, a protein that controls the cellular response to hypoxia. Parkinson’s disease affects around 6 million people, and it constitutes the fastest growing brain disorder worldwide. Therefore, it is of paramount importance to define its causes and investigate new therapies. ABSTRACT: Hypoxia is a condition characterized by insufficient tissue oxygenation, which results in impaired oxidative energy production. A reduction in cellular oxygen levels induces the stabilization of hypoxia inducible factor α (HIF-1α), master regulator of the molecular response to hypoxia, involved in maintaining cellular homeostasis and driving hypoxic adaptation through the control of gene expression. Due to its high energy requirement, the brain is particularly vulnerable to oxygen shortage. Thus, hypoxic injury can cause significant metabolic changes in neural cell populations, which are associated with neurodegeneration. Recent evidence suggests that regulating HIF-1α may ameliorate the cellular damage in neurodegenerative diseases. Indeed, the hypoxia/HIF-1α signaling pathway has been associated to several processes linked to Parkinson’s disease (PD) including gene mutations, risk factors and molecular pathways such as mitochondrial dysfunction, oxidative stress and protein degradation impairment. This review will explore the impact of hypoxia and HIF-1α signaling on these specific molecular pathways that influence PD development and will evaluate different novel neuroprotective strategies involving HIF-1α stabilization.