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

Dunn, Laura B.; Allen, Geoffrey; Mamais, Adamantios; Ling, Helen; Li, Abi; Duberley, Kate; Hargreaves, Iain P.; Pope, Simon; Holton, Janice L.; Lees, Andrew J.; Heales, Simon; Bandopadhyay, Rina

doi:10.1016/j.neurobiolaging.2013.11.001

Cited by 186 publications

(154 citation statements)

References 35 publications

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“…Nevertheless, this finding is interesting in light of the evidence that indicates that more than 50% of the PD patients are glucose intolerant and patients with diabetes who develop PD usually have a higher HY staging (40). Moreover, impaired glucose metabolism is suggested to be an early event in sporadic PD (41). Given that HNF4A plays a pivotal role in hepatic gluconeogenesis and Red and blue lines denote PD patients and HCs, respectively.…”

Section: Discussionmentioning

confidence: 85%

Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic biomarkers for Parkinson’s disease

Santiago

Potashkin

2015

Proc. Natl. Acad. Sci. U.S.A.

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Environmental and genetic factors are likely to be involved in the pathogenesis of Parkinson's disease (PD), the second most prevalent neurodegenerative disease among the elderly. Networkbased metaanalysis of four independent microarray studies identified the hepatocyte nuclear factor 4 alpha (HNF4A), a transcription factor associated with gluconeogenesis and diabetes, as a central regulatory hub gene up-regulated in blood of PD patients. In parallel, the polypyrimidine tract binding protein 1 (PTBP1), involved in the stabilization and mRNA translation of insulin, was identified as the most down-regulated gene. Quantitative PCR assays revealed that HNF4A and PTBP1 mRNAs were upand down-regulated, respectively, in blood of 51 PD patients and 45 controls nested in the Diagnostic and Prognostic Biomarkers for Parkinson's Disease. These results were confirmed in blood of 50 PD patients compared with 46 healthy controls nested in the Harvard Biomarker Study. Relative abundance of HNF4A mRNA correlated with the Hoehn and Yahr stage at baseline, suggesting its clinical utility to monitor disease severity. Using both markers, PD patients were classified with 90% sensitivity and 80% specificity. Longitudinal performance analysis demonstrated that relative abundance of HNF4A and PTBP1 mRNAs significantly decreased and increased, respectively, in PD patients during the 3-y followup period. The inverse regulation of HNF4A and PTBP1 provides a molecular rationale for the altered insulin signaling observed in PD patients. The longitudinally dynamic biomarkers identified in this study may be useful for monitoring disease-modifying therapies for PD.Parkinson's disease | HNF4A | PTBP1 | network analysis | blood biomarkers S ubstantial efforts have been devoted to the development of diagnostic strategies for Parkinson's disease (PD). In particular, changes in mRNA from cellular whole blood can facilitate the identification of dysregulated processes and diagnostic biomarkers for PD (1, 2). Several molecular signatures in blood have been identified. For example, 22 unique genes were found differentially expressed in blood of PD patients compared with healthy controls (1). Likewise, specific splice variants in blood were associated with PD in samples obtained from two independent clinical trials (2, 3). In addition, altered expression of the vitamin D receptor (VDR) in blood and reduced plasma levels of 25-hydroxy vitamin D 3 have been associated with PD (1, 4). Furthermore, plasma levels of the epidermal growth factor have been associated with cognitive decline in PD (5).Environmental stressors and genetic factors are most likely involved in the pathogenesis of PD. Among the genetic factors associated with PD, mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common cause of autosomal dominant PD (6) and a considerable risk factor in idiopathic forms of the disease (7,8). Given the complex interaction between environmental and genetic factors in sporadic PD, we integrated four independent microarray s...

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Section: Discussionmentioning

confidence: 85%

Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic biomarkers for Parkinson’s disease

Santiago

Potashkin

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Glucose metabolism is essential for brain health and dysfunction of glucose utilization in the brain represents a key component in the development of neurodegenerative disorders [95-97]. Furthermore, epidemiological studies show that hallmarks of metabolic disorders, such as glucose intolerance and/or impairment of insulin secretion, are associated with a higher risk of developing dementia or AD [98-101].…”

Section: Hne-modified Proteins Contribute To Neurodegeneration In mentioning

confidence: 99%

HNE-modified proteins in Down syndrome: Involvement in development of Alzheimer disease neuropathology

Barone

Head

Butterfield

et al. 2017

Free Radical Biology and Medicine

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Down syndrome (DS), trisomy of chromosome 21, is the most common genetic form of intellectual disability. The neuropathology of DS involves multiple molecular mechanisms, similar to AD, including the deposition of beta-amyloid (Aβ) into senile plaques and tau hyperphosphorylating in neurofibrillary tangles. Interestingly, many genes encoded by chromosome 21, in addition to being primarily linked to amyloid-beta peptide (Aβ) pathology, are responsible for increased oxidative stress (OS) conditions that also result as a consequence of reduced antioxidant system efficiency. However, redox homeostasis is disturbed by overproduction of Aβ, which accumulates into plaques across the lifespan in DS as well as in AD, thus generating a vicious cycle that amplifies OS-induced intracellular changes. The present review describes the current literature that demonstrates the accumulation of oxidative damage in DS with a focus on the lipid peroxidation by-product, 4-hydroxy-2-nonenal (HNE). HNE reacts with proteins and can irreversibly impair their functions. We suggest that among different post-translational modifications, HNE-adducts on proteins accumulate in DS brain and play a crucial role in causing the impairment of glucose metabolism, neuronal trafficking, protein quality control and antioxidant response. We hypothesize that dysfunction of these specific pathways contribute to accelerated neurodegeneration associated with AD neuropathology.

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“…The PPP consists of oxidative and non-oxidative components that, respectively, function to produce reducing equivalents (NADPH) and nucleotide precursors (ribulose-5-phosphate), and to return excess pentose-phosphates to glycolysis during times of high NADPH demand (Stincone et al, 2014). There is mounting evidence that uninterrupted NADPH supply is essential for maintenance of antioxidant defenses and the protein thiol redox state (Ben-Yoseph et al, 1996; Dunn et al, 2014; Filosa et al, 2003; Herrero-Mendez et al, 2009; Levonen et al, 2014; Li et al, 2014). Glutathione and thioredoxin are critical electron donors for ROS scavenging and protection of protein thiols, but their redox potentials strongly depend on their respective reductases, whose activities in turn depend on NADPH supplied by the oxidative PPP.…”

Section: Introductionmentioning

confidence: 99%

13C metabolic flux analysis in neurons utilizing a model that accounts for hexose phosphate recycling within the pentose phosphate pathway

Gebril

Avula

Wang

et al. 2016

Neurochemistry International

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Glycolysis, mitochondrial substrate oxidation, and the pentose phosphate pathway (PPP) are critical for neuronal bioenergetics and oxidation-reduction homeostasis, but quantitating their fluxes remains challenging, especially when processes such as hexose phosphate (i.e., glucose/fructose-6-phosphate) recycling in the PPP are considered. A hexose phosphate recycling model was developed which exploited the rates of glucose consumption, lactate production, and mitochondrial respiration to infer fluxes through the major glucose consuming pathways of adherent cerebellar granule neurons by replicating [13C]lactate labeling from metabolism of [1,2-13C2]glucose. Flux calculations were predicated on a steady-state system with reactions having known stoichiometries and carbon atom transitions. Non-oxidative PPP activity and consequent hexose phosphate recycling, as well as pyruvate production by cytoplasmic malic enzyme, were optimized by the model and found to account for 28±2 % and 7.7±0.2 % of hexose phosphate and pyruvate labeling, respectively. From the resulting fluxes, 52±6 % of glucose was metabolized by glycolysis, compared to 19±2 % by the combined oxidative/non-oxidative pentose cycle that allows for hexose phosphate recycling, and 29±8 % by the combined oxidative PPP/de novo nucleotide synthesis reactions. By extension, 62±6 % of glucose was converted to pyruvate, the metabolism of which resulted in 16±1 % of glucose oxidized by mitochondria and 46±6 % exported as lactate. The results indicate a surprisingly high proportion of glucose utilized by the pentose cycle and the reactions synthesizing nucleotides, and exported as lactate. While the in vitro conditions to which the neurons were exposed (high glucose, no lactate or other exogenous substrates) limit extrapolating these results to the in vivo state, the approach provides a means of assessing a number of metabolic fluxes within the context of hexose phosphate recycling in the PPP from a minimal set of measurements.

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

Cited by 186 publications

References 35 publications

Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic biomarkers for Parkinson’s disease

Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic biomarkers for Parkinson’s disease

HNE-modified proteins in Down syndrome: Involvement in development of Alzheimer disease neuropathology

13C metabolic flux analysis in neurons utilizing a model that accounts for hexose phosphate recycling within the pentose phosphate pathway

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