Downregulation of genes involved in metabolism and oxidative stress in the peripheral leukocytes of Huntington's disease patients.
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ABSTRACT:
SUBMITTER: Chang KH
PROVIDER: S-EPMC3459918 | biostudies-other | 2012
REPOSITORIES: biostudies-other
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Project description:Alterations in oxidative metabolism are considered to be one of the major contributors to Huntington's disease (HD) pathogenesis. However, existing data about oxidative metabolism in HD are contradictory. Here, we investigated the effect of mutant huntingtin (mHtt) on oxidative metabolism in YAC128 mice. Both mHtt and wild-type huntingtin (Htt) were associated with mitochondria and the amount of bound Htt was four-times higher than the amount of bound mHtt. Percoll gradient-purified brain synaptic and non-synaptic mitochondria as well as unpurified brain, liver and heart mitochondria, isolated from 2- and 10-month-old YAC128 mice and age-matched WT littermates had similar respiratory rates. There was no difference in mitochondrial membrane potential or ADP and ATP levels. Expression of selected nuclear-encoded mitochondrial proteins in 2- and 10-month-old YAC128 and WT mice was similar. Cultured striatal and cortical neurons from YAC128 and WT mice had similar respiratory and glycolytic activities as measured with Seahorse XF24 analyzer in medium containing 10 mm glucose and 15 mm pyruvate. In the medium with 2.5 mm glucose, YAC128 striatal neurons had similar respiration, but slightly lower glycolytic activity. Striatal neurons had lower maximal respiration compared with cortical neurons. In vivo experiments with YAC128 and WT mice showed similar O2 consumption, CO2 release, physical activity, food consumption and fasted blood glucose. However, YAC128 mice were heavier and had more body fat compared with WT mice. Overall, our data argue against respiratory deficiency in YAC128 mice and, consequently, suggest that mitochondrial respiratory dysfunction is not essential for HD pathogenesis.
| S-EPMC4527489 | biostudies-literature
Project description:BackgroundMitochondria, essential eukaryotic cells organelles defined as the "powerhouse of the cell" because of their ability to produce the vast majority of energy necessary for cellular metabolism, may have a primary role in the oxidative stress-related intracellular machinery associated to chronic kidney disease (CKD).MethodsTo better assess this research assumption, we decided to study the key factors regulating mitochondrial oxidative metabolism in CKD patients in peritoneal dialysis (PD, n = 15) using several bio-molecular methodologies.ResultsRT-PCR experiments demonstrate that the expression level of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1?) and nuclear respiratory factor-1 (NRF-1), two genes primarily involved in mitochondrial biogenesis and functions, were significantly hypo-expressed in peripheral blood mononuclear cells of PD patients compared to healthy subjects (HS, n = 15). Additionally, mRNA levels of several PGC1-? downstream target genes (TFAM, COX6C,COX7C, UQCRH and MCAD) were profoundly down-regulated in PD cells. TFAM protein analysis confirmed gene-expression results. High plasmatic concentration of Malondialdehyde found in PD patients, confirmed the contribution of the oxidative stress to these biological effects. Finally, Nuclear factor erythroid-derived 2-like 2 (NRF2 or NFE2L2), a transcription factor for numerous antioxidant/detoxifying enzymes and one of its target genes, superoxide dismutase-2 mitochondrial (SOD2) were up-regulated in PD compared to HS.ConclusionsOur results revealed, for the first time, that CKD-PD patients' PBMC, through a complex intracellular biochemical machinery, are able to modulate their mitochondrial functions probably in the attempt to reduce oxidative metabolic damage and to turn on a valuable defense cellular strategy against oxidative stress.
| S-EPMC3810143 | biostudies-literature
Project description:We previously identified a systemic metabolic defect associated with early weight loss in patients with Huntington's disease (HD), suggesting a lack of substrates for the Krebs cycle. Dietary anaplerotic therapy with triheptanoin is used in clinical trials to promote energy production in patients with peripheral and brain Krebs cycle deficit, as its metabolites - C5 ketone bodies - cross the blood-brain barrier. We conducted a short-term clinical trial in six HD patients (UHDRS (Unified Huntington Disease Rating Scale)=33+/-13, 15-49) to monitor the tolerability of triheptanoin. We also assessed peripheral markers of short-term efficacy that were shown to be altered in the early stages of HD, that is, low serum IGF1 and (31)P-NMR spectroscopy (NMRS) in muscle. At baseline, (31)P-NMRS displayed two patients with end-exercise muscle acidosis despite a low work output. On day 2, the introduction of triheptanoin was well tolerated in all patients, and in particular, there was no evidence of mitochondrial overload from triheptanoin-derived metabolites. After 4 days of triheptanoin-enriched diet, muscle pH regulation was normalized in the two patients with pretreatment metabolic abnormalities. A significant increase in serum IGF1 was also observed in all patients (205+/-60 ng/ml versus 246+/-68 ng/ml, P=0.010). This study provides a rationale for extending our anaplerotic approach with triheptanoin in HD.
| S-EPMC2987415 | biostudies-literature
Project description:Golgi stress response is emerging as a physiologic process of comparable importance to endoplasmic reticulum (ER) and mitochondrial stress responses. However, unlike ER stress, the identity of the signal transduction pathway involved in the Golgi stress response has been elusive. We show that the Golgi stressor monensin acts via the PKR-like ER kinase/Activating Transcription Factor 4 pathway. ATF4 is the master regulator of amino acid metabolism, which is induced during amino acid depletion and other forms of stress. One of the genes regulated by ATF4 is the biosynthetic enzyme for cysteine, cystathionine γ-lyase (CSE), which also plays central roles in maintenance of redox homeostasis. Huntington's disease (HD), a neurodegenerative disorder, is associated with disrupted cysteine metabolism caused by depletion of CSE leading to abnormal redox balance and stress response. Thus, restoring CSE function and cysteine disposition may be beneficial in HD. Accordingly, we harnessed the monensin-ATF4-signaling cascade to stimulate CSE expression by preconditioning cells with monensin, which restores cysteine metabolism and an optimal stress response in HD. These findings have implications for treatment of HD and other diseases associated with redox imbalance and dysregulated ATF4 signaling.
| S-EPMC5789946 | biostudies-literature
Project description:Keratoconus (KC) affects 1:2000 people and is a disorder where cornea thins and assumes a conical shape. Advanced KC requires surgery to maintain vision. The role of oxidative stress in KC remains unclear. We aimed to identify oxidative stress levels between human corneal keratocytes (HCKs), fibroblasts (HCFs) and keratoconus cells (HKCs). Cells were cultured in 2D and 3D systems. Vitamin C (VitC) and TGF-?3 (T3) were used for 4 weeks to stimulate self-assembled extracellular matrix (ECM). No T3 used as controls. Samples were analyzed using qRT-PCR and metabolomics. qRT-PCR data showed low levels of collagen I and V, as well as keratocan for HKCs, indicating differentiation to a myofibroblast phenotype. Collagen type III, a marker for fibrosis, was up regulated in HKCs. We robustly detected more than 150 metabolites of the targeted 250 by LC-MS/MS per condition and among those metabolites several were related to oxidative stress. Lactate levels, lactate/malate and lactate/pyruvate ratios were elevated in HKCs, while arginine and glutathione/oxidized glutathione ratio were reduced. Similar patterns found in both 2D and 3D. Our data shows that fibroblasts exhibit enhanced oxidative stress compared to keratocytes. Furthermore the HKC cells exhibit the greatest level suggesting they may have a myofibroblast phenotype.
| S-EPMC3980225 | biostudies-other
Project description:Huntington's disease (HD) is caused by CAG repeat expansions in the huntingtin (htt) gene, yielding proteins containing polyglutamine repeats that become misfolded and resist degradation. Previous studies demonstrated that mutant htt interferes with transcriptional programs coordinated by the peroxisome proliferator-activated receptor ? (PPAR?) coactivator 1? (PGC-1?), a regulator of mitochondrial biogenesis and oxidative stress. We tested whether restoration of PGC-1? could ameliorate the symptoms of HD in a mouse model. We found that PGC-1? induction virtually eliminated htt protein aggregation and ameliorated HD neurodegeneration in part by attenuating oxidative stress. PGC-1? promoted htt turnover and the elimination of protein aggregates by activating transcription factor EB (TFEB), a master regulator of the autophagy-lysosome pathway. TFEB alone was capable of reducing htt aggregation and neurotoxicity, placing PGC-1? upstream of TFEB and identifying these two molecules as important therapeutic targets in HD and potentially other neurodegenerative disorders caused by protein misfolding.
| S-EPMC4096245 | biostudies-literature
Project description:Huntington's disease (HD) is a hereditary autosomal dominant neurodegenerative disease. Although studies have shown that blood oxidative stress markers are dysregulated in HD patients, clinical data on the blood oxidative stress markers of HD patients is inconsistent. To better understand the pathogenesis of HD, we performed a systematic review and meta-analysis of blood oxidative stress markers in HD patients and healthy control (HC) subjects. A database search from PubMed and Web of Science identified 12 studies with 375 HD patients and 447 HC subjects in this meta-analysis. A random-effects meta-analysis showed that blood lipid peroxidation products (Hedges' g = 0.883, 95%CI = 0.637 to 1.130, p < 0.001), 8-hydroxyguanosine (Hedges' g = 1.727, 95%CI = 0.489 to 2.965, p = 0.006) levels, and the activity of glutathione peroxidase (Hedges' g = 2.026, 95%CI = 0.570 to 3.482, p = 0.006) were significantly increased in HD patients compared to controls. In contrast, reduced glutathione levels were lower in HD patients than in controls (Hedges' g = -0.611, 95%CI = -1.016 to - 0.207, p = 0.003). However, blood superoxide dismutase, cholesterol, high-density lipoproteins, low-density lipoproteins, and triglycerides did not show significant differences between cases and controls. Taken together, this study clarified the associations between blood oxidative stress markers and HD, supporting the clinical evidence that HD is accompanied by increased oxidative stress.
| S-EPMC7499314 | biostudies-literature
Project description:A mutation in the huntingtin (Htt) gene produces mutant Htt and Huntington's disease (HD), a neurodegenerative disorder. HD patients have oxidative damage in the brain, but the causes are unclear. Compared with controls, we found brain levels of NADPH oxidase (NOX) activity, which produces reactive oxygen species (ROS), elevated in human HD postmortem cortex and striatum and highest in striatum of presymptomatic individuals. Synaptosome fractions from cortex and striatum of HD(140Q/140Q) mice had elevated NOX activity at 3 months of age and a further rise at 6 and 12 months compared with synaptosomes of age-matched wild-type (WT) mice. High NOX activity in primary cortical and striatal neurons of HD(140Q/140Q) mice correlated with more ROS and neurite swellings. These features and neuronal cell death were markedly reduced by treatment with NOX inhibitors such as diphenyleneiodonium (DPI), apocynin (APO) and VAS2870. The rise in ROS levels in mitochondria of HD(140Q/140Q) neurons followed the rise in NOX activity and inhibiting only mitochondrial ROS was not neuroprotective. Mutant Htt colocalized at plasma membrane lipid rafts with gp91-phox, a catalytic subunit for the NOX2 isoform. Assembly of NOX2 components at lipid rafts requires activation of Rac1 which was also elevated in HD(140Q/140Q) neurons. HD(140Q/140Q) mice bred to gp91-phox knock-out mice had lower NOX activity in the brain and in primary neurons, and neurons had normal ROS levels and significantly improved survival. These findings suggest that increased NOX2 activity at lipid rafts is an early and major source of oxidative stress and cell death in HD(140Q/140Q) neurons.
| S-EPMC3578411 | biostudies-literature
Project description:BackgroundBecause oxidative stress affects muscle function, the underlying mechanism to explain exercise induced peripheral muscle oxidative stress in patients with chronic obstructive pulmonary disease (COPD) is clinically relevant. This study investigated whether chronic hypoxaemia in COPD worsens peripheral muscle oxidative stress and whether an abnormal muscle inflammatory process is associated with it.MethodsNine chronically hypoxaemic and nine non-hypoxaemic patients performed repeated knee extensions until exhaustion. Biopsy specimens were taken from the vastus lateralis muscle before and 48 hours after exercise. Muscle oxidative stress was evaluated by lipid peroxidation (lipofuscin and thiobarbituric acid reactive substances (TBARs)) and oxidised proteins. Inflammation was evaluated by quantifying muscle neutrophil and tumour necrosis factor (TNF)-alpha levels.ResultsWhen both groups were taken together, arterial oxygen pressure was positively correlated with quadriceps endurance time (n = 18, r = 0.57; p < 0.05). At rest, quadriceps lipofuscin inclusions were significantly greater in hypoxaemic patients than in non-hypoxaemic patients (2.9 (0.2) v 2.0 (0.3) inclusions/fibre; p < 0.05). Exercise induced a greater increase in muscle TBARs and oxidised proteins in hypoxaemic patients than in non-hypoxaemic patients (40.6 (9.1)% v 10.1 (5.8)% and 51.2 (11.9)% v 3.7 (12.2)%, respectively, both p = 0.01). Neutrophil levels were significantly higher in hypoxaemic patients than in non-hypoxaemic patients (53.1 (11.6) v 21.5 (11.2) counts per fibre x 10(-3); p < 0.05). Exercise did not alter muscle neutrophil levels in either group. Muscle TNF-alpha was not detected at baseline or after exercise.ConclusionChronic hypoxaemia was associated with lower quadriceps endurance time and worsened muscle oxidative stress at rest and after exercise. Increased muscle neutrophil levels could be a source of the increased baseline oxidative damage. The involvement of a muscle inflammatory process in the exercise induced oxidative stress of patients with COPD remains to be shown.
| S-EPMC1747208 | biostudies-literature
Project description:ObjectiveThe objective of this study was to investigate the potential molecular mechanisms of ATPase H+ transporting V1 subunit A (ATP6V1A) underlying Alzheimer's disease (AD).MethodsMicroarray expression data of human temporal cortex samples from the GSE118553 dataset were profiled to screen for differentially expressed genes (DEGs) between AD/control and ATP6V1A-low/high groups. Correlations of coexpression modules with AD and ATP6V1A were assessed by weight gene correlation network analysis (WGCNA). DEGs strongly interacting with ATP6V1A were extracted to construct global regulatory network. Further cross-talking pathways of ATP6V1A were identified by functional enrichment analysis. Diagnostic performance of ATP6V1A in AD prediction was evaluated using area under the curve (AUC) analysis.ResultsThe mean expression of ATP6V1A was significantly downregulated in AD compared with nondementia controls. A total of 1,364 DEGs were overlapped from AD/control and ATP6V1A-low/high groups. Based on these DEGs, four coexpression modules were predicted by WGCNA. The blue, brown, and turquoise modules were significantly correlated with AD and low ATP6V1A, whose DEGs were enriched in phagosome, oxidative phosphorylation, synaptic vesicle cycle, focal adhesion, and gamma-aminobutyric acidergic (GABAergic) synapse. Global regulatory network was constructed to identify the cross-talking pathways of ATP6V1A, such as synaptic vesicle cycle, phagosome, and oxidative phosphorylation. According to the AUC value of 74.2%, low ATP6V1A expression accurately predicted the occurrence of AD.ConclusionsOur findings highlighted the pleiotropic roles of low ATP6V1A in AD pathogenesis, possibly mediated by synaptic vesicle cycle, phagosome, and oxidative phosphorylation.
| S-EPMC8087993 | biostudies-literature