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Metabolic Investigations of the Molecular Mechanisms Associated with Parkinson’S Disease

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Metabolic Investigations of the Molecular Mechanisms Associated with Parkinson’S Disease H OH metabolites OH Review Metabolic Investigations of the Molecular Mechanisms Associated with Parkinson’s Disease Robert Powers 1,2,*, Shulei Lei 1, Annadurai Anandhan 3,4, Darrell D. Marshall 1, Bradley Worley 1, Ronald L. Cerny 1, Eric D. Dodds 1, Yuting Huang 1, Mihalis I. Panayiotidis 5, Aglaia Pappa 6 and Rodrigo Franco 3,4,* 1 Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA; [email protected] (S.L.); [email protected] (D.D.M.); [email protected] (B.W.); [email protected] (R.L.C.); [email protected] (E.D.D.); [email protected] (Y.H.) 2 Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA 3 Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE 68588, USA; [email protected] 4 School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68588, USA 5 Department of Applied Sciences, Northumbria University, Newcastle Upon Tyne NE1 8ST, UK; [email protected] 6 Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis 68100, Greece; [email protected] * Correspondence: [email protected] (R.P.); [email protected] (R.F.); Tel.: +01-402-472-3039 (R.P.); +01-402-472-8547 (R.F.) Academic Editors: Daniel Raftery, James Cox, Katja Dettmer and Adrian S. Culf Received: 5 April 2017; Accepted: 16 May 2017; Published: 24 May 2017 Abstract: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by fibrillar cytoplasmic aggregates of α-synuclein (i.e., Lewy bodies) and the associated loss of dopaminergic cells in the substantia nigra. Mutations in genes such as α-synuclein (SNCA) account for only 10% of PD occurrences. Exposure to environmental toxicants including pesticides and metals (e.g., paraquat (PQ) and manganese (Mn)) is also recognized as an important PD risk factor. Thus, aging, genetic alterations, and environmental factors all contribute to the etiology of PD. In fact, both genetic and environmental factors are thought to interact in the promotion of idiopathic PD, but the mechanisms involved are still unclear. In this study, we summarize our findings to date regarding the toxic synergistic effect between α-synuclein and paraquat treatment. We identified an essential role for central carbon (glucose) metabolism in dopaminergic cell death induced by paraquat treatment that is enhanced by the overexpression of α-synuclein. PQ “hijacks” the pentose phosphate pathway (PPP) to increase NADPH reducing equivalents and stimulate paraquat redox cycling, oxidative stress, and cell death. PQ also stimulated an increase in glucose uptake, the translocation of glucose transporters to the plasma membrane, and AMP-activated protein kinase (AMPK) activation. The overexpression of α-synuclein further stimulated an increase in glucose uptake and AMPK activity, but impaired glucose metabolism, likely directing additional carbon to the PPP to supply paraquat redox cycling. Keywords: Parkinson’s Disease; genetics; toxin synergy; molecular mechanisms; NMR; mass spectrometry Metabolites 2017, 7, 22; doi:10.3390/metabo7020022 www.mdpi.com/journal/metabolites Metabolites 2017, 7, 22 2 of 26 Metabolites 2017, 7, 22 2 of 26 1.1. Introduction 1.1.1.1. Parkinson’s DiseaseDisease OverviewOverview Parkinson’s diseasedisease (PD)(PD) affects affects over over one one million millio individualsn individuals in thein Unitedthe United States States and moreand more than 10than million 10 million people people worldwide worldwide [1]. PD [1]. is PD a chronic is a chronic progressive progressive neurodegenerative neurodegenerative disorder disorder that leads that toleads shaking to shaking (tremors) (tremors) and difficulty and difficulty with walking, with walking, movement, movement, and coordination. and coordination. Currently, Currently, there is nothere cure is forno cure PD or for drug PD toor stopdrug the to stop progression the prog ofression the disease, of the butdisease, there but are there treatments are treatments to manage to symptomsmanage symptoms [2]. PD is [2]. associated PD is associated with the losswith of the dopaminergic loss of dopaminergic neurons from neurons the substantia from the nigrasubstantia pars compactanigra pars withincompacta the within midbrain the (Figuremidbrain1a) (Figure [ 3,4]. The1a) [3,4]. death The of thesedeath dopaminergic of these dopaminergic neurons neurons leads to aleads deficiency to a deficiency of dopamine of dopamine in the caudate in the and caudate putamen and (“striatum”),putamen (“striatum”), which results which in results an observed in an lossobserved of muscle loss of control. muscle In control. addition In toaddition neuron to loss, neur PDon isloss, also PD characterized is also characterized by the presence by the presence of Lewy bodies—proteinof Lewy bodies—protein aggregates withinaggregates neurons within [5]. Theneur exactons cause[5]. The of PD exact is currently cause unknown,of PD is butcurrently age is anunknown, important but risk age factor is an [important6]. Individuals risk factor over the [6]. age Individuals of 60 are twiceover the as likely age of to 60 develop are twice PD as relative likely to thedevelop general PD population. relative to the Only general about population. 10% of PD cases Only have about a family10% of history PD cases of thehave disease, a family and, history to date, of 18the genetic disease, mutations and, to date, (PARK1 18 ,geneticPARK2 ,mutations etc.) have ( beenPARK1 putatively, PARK2 linked, etc.) have to PD been [7,8]. putatively Genetic alterations linked to inPDα [7,8].-synuclein Genetic [9 ,alterations10], Parkin in [11 α,-synuclein12], DJ-1 [ 13[9,10],], PINK1 Parkin [11 [11,12],], and LRRK2DJ-1 [13], [14 PINK1] have [11], been and associated LRRK2 with[14] have approximately been associated 3 to 5% with of approximately PD. Environmental 3 to 5% factors of PD. have Environmental also been linked factors to have an increase also been in thelinked incidence to an increase of PD or in risk the for incidence developing of PD PD or [15 risk]. In for fact, developing sporadic orPD idiopathic [15]. In fact, PD issporadic linked toor geneticidiopathic alterations PD is linked and occupationalto genetic alterations or environmental and occupational factors. or Exposure environmenta to pesticides,l factors. heavy Exposure metals, to infectiouspesticides, agents,heavy industrialization,metals, infectious and/or agents, dietary industrialization, factors has beenand/or associated dietary withfactors an increasedhas been occurrenceassociated ofwith PD. an Recent increased studies occurrence have demonstrated of PD. thatRecent environmental studies have exposures demonstrated modify DNAthat methylationenvironmental patterns, exposures chromatin modify structure, DNA methylation and non-coding patterns, RNA chromatin signaling (epigenetics),structure, and which non-coding might contributeRNA signaling to the (epigenetics), individual’s susceptibility which might tocontribute developing to PD.the individual’s Epigenetic patterns susceptibility defined to during developing aging andPD. developmentEpigenetic patterns can be defined altered byduring environmental aging and exposuresdevelopment [16– can18]. be Paraquat altered inducesby environmental epigenetic changesexposures by [16–18]. promoting Paraquat histone induces acetylation epigenetic [19] and, chan conversely,ges by promoting paraquat histone toxicity acetylation has been reported[19] and, toconversely, be enhanced paraquat by inhibition toxicity of DNAhas methyltransferasesbeen reported to [ 20be]. Thus,enhanced PD appears by inhibition to be multifactorial of DNA wheremethyltransferases a combination [20]. of age,Thus, genetics, PD appears and environmental to be multifactorial factors where contributes a combination to disease of developmentage, genetics, (Figureand environmental1b) [21]. factors contributes to disease development (Figure 1b) [21]. (a) (b) Figure 1. Parkinson’s disease results from dopaminergic neuron cell death in the substantia nigra: Figure 1. Parkinson’s disease results from dopaminergic neuron cell death in the substantia nigra: (a) (a) In vivo imaging of dopaminergic activity in the Parkinsonian basal ganglia shown by [18F] In vivo imaging of dopaminergic activity in the Parkinsonian basal ganglia shown by [18F] fluorodopa PET. The signal from striatum in a healthy control subject, a patient with symptomatic fluorodopa PET. The signal from striatum in a healthy control subject, a patient with symptomatic Parkinson’s disease and a twin who was asymptomatic at the time of scan but who subsequently Parkinson’s disease and a twin who was asymptomatic at the time of scan but who subsequently developed the disease. Reproduced with permission from [3]. (b) Schematic of the multiple factors that developed the disease. Reproduced with permission from [3]. (b) Schematic of the multiple factors contribute to the development of Parkinson’s disease. Both aging and environmental factors modify epigeneticthat contribute patterns, to the which development may also of enhanceParkinson’s an individual’sdisease. Both likelihood aging and ofenvironmental developing PD. factors modify epigenetic patterns, which may also enhance an individual’s likelihood of developing PD. 1.2. PD and Environmental Risk Factors 1.2. PD and Environmental Risk Factors The largest epidemiology study of PD in the USA identified a number of environmental factors The largest epidemiology study of
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