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Hypoxia Signaling in Parkinson's Disease biology Review Hypoxia Signaling in Parkinson’s Disease: There Is Use in Asking “What HIF?” Laura Lestón Pinilla 1,* , Aslihan Ugun-Klusek 1 , Sergio Rutella 2 and Luigi A. De Girolamo 1,* 1 Interdisciplinary Biomedical Research Centre, Centre for Health, Ageing and Understanding Disease, School of Science & Technology, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, UK; [email protected] 2 John van Geest Cancer Research Centre, Centre for Health, Ageing and Understanding Disease, School of Science & Technology, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, UK; [email protected] * Correspondence: [email protected] (L.L.P.); [email protected] (L.A.D.G.) 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 Citation: Lestón Pinilla, L.; Ugun-Klusek, A.; Rutella, S.; De investigate new therapies. Girolamo, L.A. Hypoxia Signaling in Parkinson’s Disease: There Is Use in Abstract: Hypoxia is a condition characterized by insufficient tissue oxygenation, which results in Asking “What HIF?”. Biology 2021, 10, impaired oxidative energy production. A reduction in cellular oxygen levels induces the stabilization 723. https://doi.org/10.3390/ of hypoxia inducible factor α (HIF-1α), master regulator of the molecular response to hypoxia, biology10080723 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 Academic Editor: Mattia Volta 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 Received: 27 June 2021 ameliorate the cellular damage in neurodegenerative diseases. Indeed, the hypoxia/HIF-1α signaling Accepted: 27 July 2021 pathway has been associated to several processes linked to Parkinson’s disease (PD) including gene Published: 29 July 2021 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 Publisher’s Note: MDPI stays neutral signaling on these specific molecular pathways that influence PD development and will evaluate with regard to jurisdictional claims in α published maps and institutional affil- different novel neuroprotective strategies involving HIF-1 stabilization. iations. Keywords: Parkinson’s disease; hypoxia; HIF-1; autophagy; proteasome; mitochondria; oxidative stress Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. 1. Systemic and Cellular Response to Hypoxia This article is an open access article distributed under the terms and Oxygen is required for most organisms to produce the energy necessary to fulfil conditions of the Creative Commons cellular metabolic demands. Thus, when facing hypoxic stress, cells and organisms undergo Attribution (CC BY) license (https:// several molecular and systemic modifications resulting in adaptation and survival. creativecommons.org/licenses/by/ Low oxygen saturation within the blood circulatory system is sensed by neuron-like 4.0/). glomus cells located in the carotid body [1], whilst neuroepithelial body cells, situated in Biology 2021, 10, 723. https://doi.org/10.3390/biology10080723 https://www.mdpi.com/journal/biology Biology 2021, 10, 723 2 of 28 pulmonary airways, detect oxygen fluctuations in inspired air [2]. Detection of hypoxia triggers a cardiorespiratory response within seconds, consisting of increased pulmonary ventilation and vasoconstriction, elevated heart rate and general vasodilation in order to maximize gas exchange and facilitate oxygen delivery to tissues [3]. Biology 2021, 10, x FOR PEER REVIEW The swift systemic adjustment is followed by a specific2 of 29 cellular response, directed by the principal regulator of the transcriptional response to hypoxia, HIF-1. HIF-1 is a basic helix-loop-helix (bHLH) PAS heterodimer comprising a nuclear constitutively expressedLow oxygen HIF-1 saturationβ subunit within the and blood a HIF-1circulatoryα subunit, system is sensed whose by neuron expression-like is precisely modulated glomus cells located in the carotid body [1], whilst neuroepithelial body cells, situated in bypulmonary cellular airways, oxygen detect tension oxygen fluctuations [4] (Figure in inspired1). The air bHLH[2]. Detection domain of hypoxia mediates HIF-1 dimerization alongtriggers a with cardiorespiratory the PAS response domain within and seconds, both consisting subunits of increased contain pulmonary transactivation domains (TAD), ventilation and vasoconstriction, elevated heart rate and generalα vasodilation in order to necessarymaximize gas exchange to switch and facilitate on HIF-1 oxygen [ 5delivery]. The to tissuessubunit [3]. of HIF-1 presents a distinct oxygen- dependentThe swift systemic degradation adjustment domainis followed by (ODDD), a specific cellular which response, controls directed its by stability [6]. In normoxia, HIF-1the principalα has regulator a remarkably of the transcriptional short response half-life, to hypoxia, as it isHIF continuously-1. HIF-1 is a basic synthesized de novo and helix-loop-helix (bHLH) PAS heterodimer comprising a nuclear constitutively expressed degradedHIF-1β subunit via and thea HIF ubiquitin-proteasome-1α subunit, whose expression systemis precisely (UPS).modulated HIF-1 by cel-α is ubiquitinated by Von Hippellular oxygen Lindau tension factor [4] (Figure (pVHL), 1). The thebHLH recognition domain mediates component HIF-1 dimerization of an E3 ubiquitin-protein ligase, along with the PAS domain and bothα subunits contain transactivation domains (TAD), whichnecessary interacts to switch withon HIF HIF-1-1 [5]. Theby α recognizingsubunit of HIF-1 two presents conserved a distinct hydroxylatedoxy- proline residues ongen- itsdependent ODDD degradation (P402 and domain P564 (ODDD), in human which HIF-1controlsα )[its7 ].stability These [6] prolines. In are hydroxylated by HIF-1normoxia, prolyl HIF-1α hydroxylases has a remarkably (PHDs)short half-life, that as requireit is continuously a significant synthesized oxygen de concentration to carry novo and degraded via the ubiquitin-proteasome system (UPS). HIF-1α is ubiquitinated outby Von their Hippel enzymatic Lindau factor function (pVHL), [8 the]. Therefore,recognition component insufficient of an oxygen E3 ubiqui- impairs PHD hydroxylation function,tin-protein ligase, disrupting which interacts HIF-1 withα interaction HIF-1α by recognizing with pVHL two conserved and allowing hydrox- accumulation of HIF-1α, ylated proline residues on its ODDD (P402 and P564 in human HIF-1α) [7]. Theseβ pro- whichlines are ishydroxylated then able by HIF to- enter1 prolyl thehydroxylases nucleus (PHDs) and that bind require HIF-1 a significantto assemble transcriptionally activeoxygen concentration HIF-1. In hypoxia,to carry out HIF-1their enzymatic acts as function a transcription [8]. Therefore, factor insufficient mainly by binding to hypoxia responseoxygen impairs elements PHD hydroxylation (HRE) in function, gene promoters, disrupting HIF typically-1α interaction containing with pVHL the consensus sequence 50- and allowing accumulation0 of HIF-1α, which is then able to enter the nucleus and bind (A/G)CGTG-3HIF-1β to assemble transcriptionally, in the presence active ofHIF the-1. In transcriptional hypoxia, HIF-1 acts coactivators as a transcrip- CBP and p300, facilitating thetion expressionfactor mainly by of binding several to hypoxia genes response [9]. However, elements (HRE) when in gene oxygen promoters, is available, factor inhibiting typically containing the consensus sequence 5′-(A/G)CGTG-3′, in the presence of the α HIF-1transcriptional (FIH), coactivators hydroxylates CBP and anp300, asparagine facilitating the residueexpression inof several the C-TAD genes [9]. of HIF-1 (N803 in human HIF-1However,α), when blocking oxygen itsis available, interaction factor i withnhibiting the HIF coactivators,-1 (FIH), hydroxylates thereby an as- preventing HIF-1 mediated geneparagine expression residue in the [C10-TAD]. Althoughof HIF-1α (N803 both in human FIHs HIF and-1α), PHDs,blocking its are interac- inactivated by hypoxia, their tion with the coactivators, thereby preventing HIF-1 mediated gene expression [10]. activityAlthough both can FIHs be inhibitedand PHDs, are by inactivated iron chelators by hypoxia, like theirdeferoxamine activity can be inhibited
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