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...

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Bibliographic Details
Published in:Neurobiology of aging 2014-05, Vol.35 (5), p.1111-1115
Main Authors: Dunn, Laura, Allen, George FG, Mamais, Adamantios, Ling, Helen, Li, Abi, Duberley, Kate E, Hargreaves, Iain P, Pope, Simon, Holton, Janice L, Lees, Andrew, Heales, Simon J, Bandopadhyay, Rina
Format: Article
Language:English
Subjects:
Aged
Aged, 80 and over
Animals
Antioxidants - metabolism
Brief Communication
Cell Death
Cerebellum - enzymology
Cerebellum - metabolism
Dopaminergic Neurons - pathology
Female
Glucose - metabolism
Glucosephosphate Dehydrogenase - metabolism
Humans
Internal Medicine
Male
NADP - metabolism
NADPH
Neurodegeneration
Neurology
Neurons - metabolism
Parkinson Disease - etiology
Parkinson Disease - metabolism
Parkinson Disease - pathology
Parkinson's disease
Pentose Phosphate Pathway - physiology
Pentose-phosphate pathway
Phosphogluconate Dehydrogenase - metabolism
Putamen - enzymology
Putamen - metabolism
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Summary: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.
ISSN:0197-4580
1558-1497
DOI:10.1016/j.neurobiolaging.2013.11.001