Downregulation of Genes Involved in Metabolism and Oxidative Stress in the Peripheral Leukocytes of Huntington's Disease Patients

Chang, Kuo‐Hsuan; Chen, Yi‐Chun; Wu, Yih‐Ru; Lee, Wan-Fen; Chen, Chiung‐Mei

doi:10.1371/journal.pone.0046492

Cited by 28 publications

(14 citation statements)

References 48 publications

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“…Postmortem analysis also revealed that the levels of mitochondrial enzymes involved in oxidative phosphorylation are also depressed in the brains of HD patients, especially the basal ganglia (Chen et al, 2007;Duran et al, 2010). In addition to reports of increased oxidative stress (Browne et al, 1997;Browne and Beal, 2006;del Hoyo et al, 2006;Chen et al, 2007;Klepac et al, 2007;Chang et al, 2012) and mitochondrial dysfunction (Browne, 2008;Damiano et al, 2010;Kim et al, 2010), chronic inflammation is also evident in HD (Pavese et al, 2006;Tai et al, 2007;Bjorkqvist et al, 2008;Politis et al, 2011). Inflammation appears to be an early event in the pathogenesis of HD, and PET imaging has revealed increased microglial activation that is already evident in the striatum and cortex of presymptomatic HD carriers (Tai et al, 2007;Politis et al, 2011).…”

Section: Nrf2 and Hdmentioning

confidence: 93%

NRF2 as a Therapeutic Target in Neurodegenerative Diseases

2020

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Increased reactive oxygen species production and oxidative stress have been implicated in the pathogenesis of numerous neurodegenerative conditions including among others Alzheimer's disease, Parkinson's disease, Huntington's disease, Friedrich's ataxia, multiple sclerosis, and stroke. The endogenous antioxidant response pathway protects cells from oxidative stress by increasing the expression of cytoprotective enzymes and is regulated by the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2). In addition to regulating the expression of antioxidant genes, NRF2 has also been shown to exert anti-inflammatory effects and modulate both mitochondrial function and biogenesis. This is because mitochondrial dysfunction and neuroinflammation are features of many neurodegenerative diseases as well NRF2 has emerged as a promising therapeutic target. Here, we review evidence for a beneficial role of NRF2 in neurodegenerative conditions and the potential of specific NRF2 activators as therapeutic agents.

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Section: Nrf2 and Hdmentioning

confidence: 93%

NRF2 as a Therapeutic Target in Neurodegenerative Diseases

2020

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“…Multiple alterations in gene expression patterns, mainly using microarray technology and the further validation of selected genes, have been shown in the peripheral tissues of HD patients and in the peripheral blood of mouse models of HD [ 17 – 24 ]. For instance, variation in the expression level of genes involved in energy metabolism, oxidative stress and inflammatory response in peripheral leukocytes of HD patients with respect to control individuals have been reported [ 21 – 23 ]. Different studies have suggested that the toxic mHTT gain of function may involve disturbed glutamate-induced Ca 2+ signalling in MSNs [ 9 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Evaluating the SERCA2 and VEGF mRNAs as Potential Molecular Biomarkers of the Onset and Progression in Huntington’s Disease

et al. 2015

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Abnormalities of intracellular Ca2+ homeostasis and signalling as well as the down-regulation of neurotrophic factors in several areas of the central nervous system and in peripheral tissues are hallmarks of Huntington’s disease (HD). As there is no therapy for this hereditary, neurodegenerative fatal disease, further effort should be made to slow the progression of neurodegeneration in patients through the definition of early therapeutic interventions. For this purpose, molecular biomarker(s) for monitoring disease onset and/or progression and response to treatment need to be identified. In the attempt to contribute to the research of peripheral candidate biomarkers in HD, we adopted a multiplex real-time PCR approach to analyse the mRNA level of targeted genes involved in the control of cellular calcium homeostasis and in neuroprotection. For this purpose we recruited a total of 110 subjects possessing the HD mutation at different clinical stages of the disease and 54 sex- and age-matched controls. This study provides evidence of reduced transcript levels of sarco-endoplasmic reticulum-associated ATP2A2 calcium pump (SERCA2) and vascular endothelial growth factor (VEGF) in peripheral blood mononuclear cells (PBMCs) of manifest and pre-manifest HD subjects. Our results provide a potentially new candidate molecular biomarker for monitoring the progression of this disease and contribute to understanding some early events that might have a role in triggering cellular dysfunctions in HD.

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“…Several kinds of abnormalities including increased cytokines, mitochondrial dysfunction, increased oxidative stress, aberrant adenosine A2A receptor function, reduced phosphorylated serine-threonine protein kinase 1 (Akt), increased pro-catabolic serum metabolites, elevated serum 8OH2’dG, deficient fatty acid amide hydrolase activity, energy deficit, and alteration of phosphatidylcholine in peripheral blood of HD patients have been reported [ 9 , 10 , 27 , 34 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ], whereas only a few showed a positive correlation with disease severity or stage [ 9 , 10 , 27 , 34 , 51 , 53 , 56 , 57 ]. Notably, our study has shown that Aco2 activity in the striatum of R6/2 mice could be restored by the anti-oxidant NAC that also improved motor performance of R6/2 mice.…”

Section: Discussionmentioning

confidence: 99%

Altered Aconitase 2 Activity in Huntington’s Disease Peripheral Blood Cells and Mouse Model Striatum

Chen

Chang

2017

IJMS

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Huntington’s disease (HD) is caused by an unstable cytosine adenine guanine (CAG) trinucleotide repeat expansion encoding a polyglutamine tract in the huntingtin protein. Previously, we identified several up- and down-regulated protein molecules in the striatum of the Hdh(CAG)150 knock-in mice at 16 months of age, a mouse model which is modeling the early human HD stage. Among those molecules, aconitase 2 (Aco2) located in the mitochondrial matrix is involved in the energy generation and susceptible to increased oxidative stress that would lead to inactivation of Aco2 activity. In this study, we demonstrate decreased Aco2 protein level and activity in the brain of both Hdh(CAG)150 and R6/2 mice. Aco2 activity was decreased in striatum of Hdh(CAG)150 mice at 16 months of age as well as R6/2 mice at 7 to 13 weeks of age. Aco2 activity in the striatum of R6/2 mice could be restored by the anti-oxidant, N-acetyl-l-cysteine, supporting that decreased Aco2 activity in HD is probably caused by increased oxidative damage. Decreased Aco2 activity was further found in the peripheral blood mononuclear cells (PBMC) of both HD patients and pre-symptomatic HD mutation (PreHD) carriers, while the decreased Aco2 protein level of PBMC was only present in HD patients. Aco2 activity correlated significantly with motor score, independence scale, and functional capacity of the Unified Huntington’s Disease Rating Scale as well as disease duration. Our study provides a potential biomarker to assess the disease status of HD patients and PreHD carriers.

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Downregulation of Genes Involved in Metabolism and Oxidative Stress in the Peripheral Leukocytes of Huntington's Disease Patients

Cited by 28 publications

References 48 publications

NRF2 as a Therapeutic Target in Neurodegenerative Diseases

NRF2 as a Therapeutic Target in Neurodegenerative Diseases

Evaluating the SERCA2 and VEGF mRNAs as Potential Molecular Biomarkers of the Onset and Progression in Huntington’s Disease

Altered Aconitase 2 Activity in Huntington’s Disease Peripheral Blood Cells and Mouse Model Striatum

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