Dysregulation of glucose metabolism is an early event in sporadic Parkinson's disease

Laura Dunn; George F. G. Allen; Adamantios Mamais; Helen Ling; Abi Li; Kate E. Duberley; Iain P. Hargreaves; Simon Pope; Janice L. Holton; Andrew Lees; Simon J. Heales; Rina Bandopadhyay

doi:10.1016/j.neurobiolaging.2013.11.001

Dysregulation of glucose metabolism is an early event in sporadic Parkinson's disease

Laura Dunn (Lead / Corresponding author), George F. G. Allen, Adamantios Mamais, Helen Ling, Abi Li, Kate E. Duberley, Iain P. Hargreaves, Simon Pope, Janice L. Holton, Andrew Lees, Simon J. Heales, Rina Bandopadhyay

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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.

Original language	English
Pages (from-to)	1111-1115
Number of pages	5
Journal	Neurobiology of Aging
Volume	35
Issue number	5
DOIs	https://doi.org/10.1016/j.neurobiolaging.2013.11.001
Publication status	Published - May 2014

Keywords

Aged
Aged, 80 and over
Animals
Antioxidants
Cell Death
Cerebellum
Dopaminergic Neurons
Female
Glucose
Glucosephosphate Dehydrogenase
Humans
Male
NADP
Neurons
Parkinson Disease
Pentose Phosphate Pathway
Phosphogluconate Dehydrogenase
Putamen

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.neurobiolaging.2013.11.001

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Final published version, 581 KBLicence: CC BY-NC-ND

A Systematic Investigation into the Pathogenesis and Course of Parkinson's Syndrome (Wellcome Trust and MRC Neurodegenerative Diseases Initiative) (Joint with University College London)
Alessi, D. (Investigator)
Medical Research Council
1/09/10 → 31/08/15
Project: Research

Cite this

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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.",

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author = "Laura Dunn and Allen, {George F. G.} and Adamantios Mamais and Helen Ling and Abi Li and Duberley, {Kate E.} and Hargreaves, {Iain P.} and Simon Pope and Holton, {Janice L.} and Andrew Lees and Heales, {Simon J.} and Rina Bandopadhyay",

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AU - Dunn, Laura

AU - Allen, George F. G.

AU - Mamais, Adamantios

AU - Ling, Helen

AU - Li, Abi

AU - Duberley, Kate E.

AU - Hargreaves, Iain P.

AU - Pope, Simon

AU - Holton, Janice L.

AU - Lees, Andrew

AU - Heales, Simon J.

AU - Bandopadhyay, Rina

PY - 2014/5

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N2 - 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.

AB - 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.

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KW - Animals

KW - Antioxidants

KW - Cell Death

KW - Cerebellum

KW - Dopaminergic Neurons

KW - Female

KW - Glucose

KW - Glucosephosphate Dehydrogenase

KW - Humans

KW - Male

KW - NADP

KW - Neurons

KW - Parkinson Disease

KW - Pentose Phosphate Pathway

KW - Phosphogluconate Dehydrogenase

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EP - 1115

JO - Neurobiology of Aging

JF - Neurobiology of Aging

IS - 5

ER -

Dysregulation of glucose metabolism is an early event in sporadic Parkinson's disease

Abstract

Keywords

UN SDGs

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Projects

A Systematic Investigation into the Pathogenesis and Course of Parkinson's Syndrome (Wellcome Trust and MRC Neurodegenerative Diseases Initiative) (Joint with University College London)

Cite this