Hypoxia Pathways in Parkinson's Disease: From Pathogenesis to Therapeutic Targets

Abstract

The human brain is highly dependent on oxygen, utilizing approximately 20% of the body's oxygen at rest. Oxygen deprivation to the brain can lead to loss of consciousness within seconds and death within minutes. Recent studies have identified regions of the brain with spontaneous episodic hypoxia, referred to as "hypoxic pockets". Hypoxia can also result from impaired blood flow due to conditions such as heart disease, blood clots, stroke, or hemorrhage, as well as from reduced oxygen intake or excessive oxygen consumption caused by factors like low ambient oxygen, pulmonary diseases, infections, inflammation, and cancer. Severe hypoxia in the brain can manifest symptoms similar to Parkinson's disease (PD), including cerebral edema, mood disturbances, and cognitive impairments. Additionally, the development of PD appears to be closely associated with hypoxia and hypoxic pathways. This review seeks to investigate the molecular interactions between hypoxia and PD, emphasizing the pathological role of hypoxic pathways in PD and exploring their potential as therapeutic targets.

Keywords: DJ-1; Parkinson’s disease; hypoxia; hypoxia pathways; leucine-rich repeat kinase 2 (LRRK2); neurodegenerative diseases; transmembrane protein 175.

Figure 1

The HIF pathway in hypoxia. Under conditions of sufficient oxygen, PHD and FIH hydroxylate HIF-1α. Hydroxylated HIF-1α is subsequently recognized by VHL, leading to its ubiquitination and degradation. As a result, the concentration of HIF-1α remains very low. In moderate hypoxia, only FIH hydroxylates HIF-1α, allowing HIF-1α to translocate into the nucleus, where it binds with HIF-1β to form the HIF complex. This complex then binds to HREs in the genome, initiating transcription of target genes. In severe hypoxia, unhydroxylated HIF-1α not only enters the nucleus and binds to HIF-1β but also interacts with the coactivator p300. This interaction enhances the transcription of downstream regulatory genes. Abbreviations: PD: Parkinson’s disease; HIF-1α: hypoxia inducing factor-1α; FIH: factor inhibiting HIF; PHD: hypoxia-inducible factor prolyl hydroxylase; pVHL: von Hippel–Lindau protein; Ub: ubiquitin; Proteasome: 26S proteasome; HIF-1β: hypoxia inducing factor-1β; CBP/P300: the coactivator CBP/P300; HER: hypoxia response elements; TH: tyrosine hydroxylase; DAT: dopamine transporter; O₂: oxygen.

Figure 2

The Nrf2/HO-1 pathway in hypoxia. In the cytoplasm, KEAP1 forms a ubiquitin E3 ligase complex with CUL3 to polyubiquitinate NRF2, leading to its rapid degradation by the proteasomal system. Under oxidative stress, NRF2 is released from KEAP1-mediated inhibition. NRF2 translocates to the nucleus, where it heterodimerizes with the small Maf protein. Then, this NRF2-Maf complex binds to the ARE in the genome, allowing the expression of a series of downstream protective phase II detoxification enzyme and antioxidant enzyme genes and proteins, such as HO-1. Abbreviations: Nrf2: nuclear factor erythroid 2-related factor 2; sMAF: myeloma-associated factors; ARE: antioxidant response element; HO-1: heme oxygenase-1; UPS: ubiquitin proteasome system; MPTP/MPP+: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-Methyl-4-phenylpyridinium; α-syn: α-synuclein; Keap1: Kelch-like ECH-associated protein 1; Cul3: Cullin-3; Ub: ubiquitin; Proteasome: 26S proteasome.

Figure 3

Hypoxia-induced neuronal damage and PD. Three pieces of evidence of hypoxia-induced neuronal damage and Parkinson’s disease: (1) the susceptibility of dopaminergic neurons to hypoxia, (2) clinical evidence of hypoxia in PD patients, and (3) the impact of cellular oxygen deficit on PD progression. Abbreviations: ROS: reactive oxygen species; L-DOPA: L-3,4-dihydroxyphenylalanine; Ub: ubiquitin; HIF-2α: hypoxia inducing factor-2α; SNpc: substantia nigra pars compacta; BDNF: brain-derived neurotrophic factor.

Figure 4

Hypoxia contributes to PD. HIF-1α influences the development of PD through multiple pathways, including the accumulation of α-syn, mitochondrial dysfunction, lysosomal damage, and alterations in receptor and neurotransmitter systems. Abbreviations: HIF-1α: hypoxia inducing factor-1α; EV: extracellular vesicle; ILVs: intracavitary vesicles; ATP6V1A: ATPase H⁺ transporting V1 subunit A; α-syn: α-synuclein.

Figure 5

The role of five PD-related genes in hypoxia. The PRKN, PINK1, LRRK2, DJ-1, and TMEM175 genes play significant roles in the onset and progression of PD. Under certain conditions, these genes interact with HIF-1α, influencing the disease’s development. Abbreviations: PRKN: Parkin RBR E3 ubiquitin protein ligase; LRRK2: Leucine-rich repeat kinase 2; PINK1: PTEN-induced putative kinase 1; DJ-1: PARK7, Parkinson protein 7; TMEM175: Transmembrane Protein 175; HER: hypoxia response elements; HIF: hypoxia inducing factor; pVHL: von Hippel–Lindau; PI3K: phosphatidylin-ositol-3-kinase; AKT: protein kinase B, PKB; TBI: traumatic brain injury; p-α-syn: phosphorylated α-Syn; I/R: ischemia–reperfusion; NO: nitric oxide; Ub: ubiquitin; Proteasome: 26S proteasome.