title: Dysregulation of glucose metabolism is an early event in sporadic Parkinson's disease.
abstract: Unlike most other cell types, neurons preferentially metabolize glucose via the pentose phosphate pathway (PPP) to maintain their antioxidant status. Inhibiting the PPP in neuronal cell models causes cell death. In rodents, inhibition of this pathway causes selective dopaminergic cell death leading to motor deficits resembling parkinsonism. Using postmortem human brain tissue, we characterized glucose metabolism via the PPP in sporadic Parkinson's disease (PD), Alzheimer's disease (AD), and controls. AD brains showed increased nicotinamide adenine dinucleotide phosphate (NADPH) production in areas affected by disease. In PD however, increased NADPH production was only seen in the affected areas of late-stage cases. Quantifying PPP NADPH-producing enzymes glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase by enzyme-linked immunosorbent assay, showed a reduction in the putamen of early-stage PD and interestingly in the cerebellum of early and late-stage PD. Importantly, there was no decrease in enzyme levels in the cortex, putamen, or cerebellum of AD. Our results suggest that down-regulation of PPP enzymes and a failure to increase antioxidant reserve is an early event in the pathogenesis of sporadic PD.
authors.affiliation: Reta Lila Weston Laboratories, UCL Institute of Neurology, London, UK. Electronic address: laura.dunn11@uclmail.net.
authors.forename: Laura
authors.initials: L
authors.lastname: Dunn
authors.affiliation: MRC Protein Phosphorylation Unit. University of Dundee, Dundee, UK.
authors.forename: George Fg
authors.initials: GF
authors.lastname: Allen
authors.affiliation: Reta Lila Weston Laboratories, UCL Institute of Neurology, London, UK.
authors.forename: Adamantios
authors.initials: A
authors.lastname: Mamais
authors.affiliation: Reta Lila Weston Laboratories, UCL Institute of Neurology, London, UK; Queen Square Brain Bank, UCL Institute of Neurology, London, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Ling
authors.affiliation: Queen Square Brain Bank, UCL Institute of Neurology, London, UK.
authors.forename: Abi
authors.initials: A
authors.lastname: Li
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Kate E
authors.initials: KE
authors.lastname: Duberley
authors.affiliation: Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Iain P
authors.initials: IP
authors.lastname: Hargreaves
authors.affiliation: Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Pope
authors.affiliation: Queen Square Brain Bank, UCL Institute of Neurology, London, UK.
authors.forename: Janice L
authors.initials: JL
authors.lastname: Holton
authors.affiliation: Reta Lila Weston Laboratories, UCL Institute of Neurology, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lees
authors.affiliation: Chemical Pathology Department, Great Ormond Street Hospital, London, UK; Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, UK; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Heales
authors.affiliation: Reta Lila Weston Laboratories, UCL Institute of Neurology, London, UK.
authors.forename: Rina
authors.initials: R
authors.lastname: Bandopadhyay
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D016923:Cell Death; D002531:Cerebellum / Q000201:enzymology / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000473:pathology; D005260:Female; D005947:Glucose / Q000378:metabolism*; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D006801:Humans; D008297:Male; D009249:NADP / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D010427:Pentose Phosphate Pathway / Q000502:physiology; D010734:Phosphogluconate Dehydrogenase / Q000378:metabolism; D011699:Putamen / Q000201:enzymology / Q000378:metabolism
chemical_list: D000975:Antioxidants; D009249:NADP; D010734:Phosphogluconate Dehydrogenase; D005954:Glucosephosphate Dehydrogenase; D005947:Glucose
keywords: Glucose metabolism; NADPH; Neurodegeneration; Parkinson's disease; Pentose-phosphate pathway