Increased Plasma Heme Oxygenase-1 Levels in Patients With Early-Stage Parkinson’s Disease

Introduction: Heme oxygenase-1 (HO-1) is a 32 kDa stress-response protein implicated in the pathogenesis of Parkinson’s disease (PD). Biliverdin is derived from heme through a reaction mediated by HO-1 and protects cells from oxidative stress. However, iron and carbon monoxide produced by the catabolism of HO-1 exert detrimental effects on patients with PD. The purpose of this study was to determine whether plasma HO-1 levels represent a biomarker of PD and to further explore the underlying mechanism of increased HO-1 levels by applying voxel-based morphometry (VBM).Methods: We measured plasma HO-1 levels using an enzyme-linked immunosorbent assay (ELISA) in 156 subjects, including 81 patients with early- and advanced-stage PD and 75 subjects without PD. The analyses were adjusted to control for confounders such as age, sex, and medication. We analyzed T1-weighted magnetic resonance imaging (MRI) data from 74 patients with PD using VBM to elucidate the association between altered brain volumes and HO-1 levels. Then, we compared performance on MMSE sub-items between PD patients with low and high levels of HO-1 using Mann-Whitney U tests.Results: Plasma HO-1 levels were significantly elevated in PD patients, predominantly those with early-stage PD, compared with controls (p < 0.05). The optimal cutoff value for patients with early PD was 2.245 ng/ml HO-1 [area under the curve (AUC) = 0.654]. Plasma HO-1 levels were unaffected by sex, age, and medications (p > 0.05). The right hippocampal volume was decreased in the subset of PD patients with high HO-1 levels (p < 0.05). A weak correlation was observed between right hippocampal volume and plasma HO-1 levels (r = −0.273, p = 0.018). There was no difference in total MMSE scores between the low- and high-HO-1 groups (p > 0.05), but the high-HO-1 group had higher language scores than the low-HO-1 group (p < 0.05).Conclusions: Plasma HO-1 levels may be a promising biomarker of early PD. Moreover, a high plasma concentration of the HO-1 protein is associated with a reduction in right hippocampal volume.

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Genetic analysis of heme oxygenase-1 (HO-1) in German Parkinson’s disease patients

Journal of Neural Transmission ◽

10.1007/s00702-009-0237-6 ◽

2009 ◽

Vol 116 (7) ◽

pp. 853-859 ◽

Cited By ~ 14

Author(s):

Claudia Funke ◽

Juergen Tomiuk ◽

Olaf Riess ◽

Daniela Berg ◽

Anne S. Soehn

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Genetic Analysis ◽

Heme Oxygenase ◽

Heme Oxygenase 1

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Heme Oxygenase-1-Mediated Autophagy Protects against Oxidative Damage in Rat Nucleus Pulposus-Derived Mesenchymal Stem Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/9349762 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14

Author(s):

Sheng Chen ◽

Sheng Liu ◽

Lei Zhao ◽

Hui Lin ◽

Kaige Ma ◽

...

Keyword(s):

Oxidative Stress ◽

Oxidative Damage ◽

Cell Viability ◽

Nucleus Pulposus ◽

Heme Oxygenase ◽

Early Stage ◽

Underlying Mechanism ◽

Research Direction ◽

Heme Oxygenase 1 ◽

Ivd Degeneration

Although endogenous nucleus pulposus-derived mesenchymal stem cell- (NPMSC-) based regenerative medicine has provided promising repair strategy for intervertebral disc (IVD) degeneration, the hostile microenvironments in IVD, including oxidative stress, can negatively affect the survival and function of the NPMSCs and severely hinder the endogenous repair process. Therefore, it is of great importance to reveal the mechanisms of the endogenous repair failure caused by the adverse microenvironments in IVD. The aim of this study was to investigate the effect of oxidative stress on the rat NPMSCs and its underlying mechanism. Our results demonstrated that oxidative stress inhibited cell viability, induced apoptosis, and increased the production of reactive oxygen species (ROS) in NPMSCs. In addition, the results showed that the expression level of heme oxygenase-1 (HO-1) increased at an early stage but decreased at a late stage when NPMSCs were exposed to oxidative stress, and the oxidative damages of NPMSCs could be partially reversed by promoting the expression of HO-1. Further mechanistic analysis indicated that the protective effect of HO-1 against oxidative damage in NPMSCs was mediated by the activation of autophagy. Taken together, our study revealed that oxidative stress could inhibit cell viability, induce apoptosis, and increase ROS production in NPMSCs, and HO-1-mediated autophagy might act as a protective response to the oxidative damage. These findings might enhance our understanding on the mechanism of the endogenous repair failure during IVD degeneration and provide novel research direction for the endogenous repair of IVD degeneration.

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Alterations of Erythrocytic Phosphorylated Alpha-Synuclein in Different Subtypes and Stages of Parkinson's Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.623977 ◽

2021 ◽

Vol 13 ◽

Author(s):

Xu-Ying Li ◽

Wei Li ◽

Xin Li ◽

Xu-Ran Li ◽

Linjuan Sun ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Duration ◽

Late Onset ◽

Area Under The Curve ◽

Alpha Synuclein ◽

Enzyme Linked Immunosorbent Assay ◽

Healthy Controls ◽

Olfactory Loss ◽

Potential Biomarker

Serine 129-phosphorylated alpha-synuclein (pS-α-syn) is a major form of α-syn relevant to the pathogenesis of Parkinson's disease (PD), which has been recently detected in red blood cells (RBCs). However, alterations of RBC-derived pS-α-syn (pS-α-syn-RBC) in different subtypes and stages of PD remains to be investigated. In the present study, by using enzyme-linked immunosorbent assay (ELISA) to measure pS-α-syn-RBC, we demonstrated significantly higher levels of pS-α-syn-RBC in PD patients than in healthy controls. pS-α-syn-RBC separated the patients well from the controls, with a sensitivity of 93.39% (95% CI: 90.17–95.81%), a specificity of 93.11% (95% CI: 89.85–95.58%), and an area under the curve (AUC) of 0.96. Considering motor subtypes, the levels of pS-α-syn-RBC were significantly higher in late-onset than young-onset PD (p = 0.013) and in those with postural instability and gait difficulty than with tremor-dominant (TD) phenotype (p = 0.029). In addition, the levels of pS-α-syn-RBC were also different in non-motor subtypes, which were significantly lower in patients with cognitive impairment (p = 0.012) and olfactory loss (p = 0.004) than in those without such symptoms. Moreover, the levels of pS-α-syn-RBC in PD patients were positively correlated with disease duration and Hoehn & Yahr stages (H&Y) (p for trend =0.02 and <0.001) as well as UPDRS III (R2 = 0.031, p = 0.0042) and MoCA scores (R2 = 0.048, p = 0.0004). The results obtained suggest that pS-α-syn-RBC can be used as a potential biomarker for not only separating PD patients from healthy controls but also predicting the subtypes and stages of PD.

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Synergistic effect of two oxidative stress-related genes (heme oxygenase-1 and GSK3β) on the risk of Parkinson’s disease

European Journal of Neurology ◽

10.1111/j.1468-1331.2009.02908.x ◽

2009 ◽

Vol 17 (5) ◽

pp. 760-762 ◽

Cited By ~ 18

Author(s):

J. Infante ◽

I. García-Gorostiaga ◽

P. Sánchez-Juan ◽

M. Sierra ◽

J. L. Martín-Gurpegui ◽

...

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Synergistic Effect ◽

Heme Oxygenase ◽

Heme Oxygenase 1 ◽

Stress Related Genes

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Deletion ofHerpud1Enhances Heme Oxygenase-1 Expression in a Mouse Model of Parkinson’s Disease

Parkinson s Disease ◽

10.1155/2016/6163934 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Thuong Manh Le ◽

Koji Hashida ◽

Hieu Minh Ta ◽

Mika Takarada-Iemata ◽

Koichi Kokame ◽

...

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mouse Model ◽

Heme Oxygenase ◽

Active Form ◽

Heme Oxygenase 1 ◽

Protein Levels ◽

The Status ◽

Mptp Administration

Herp is an endoplasmic reticulum- (ER-) resident membrane protein that plays a role in ER-associated degradation. We studied the expression of Herp and its effect on neurodegeneration in a mouse model of Parkinson’s disease (PD), in which both the oxidative stress and the ER stress are evoked. Eight hours after administering a PD-related neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to mice, the expression of Herp increased at both the mRNA and the protein levels. Experiments usingHerpud1+/+andHerpud1−/−mice revealed that the status of acute degeneration of nigrostriatal neurons and reactive astrogliosis was comparable between two genotypes after MPTP injection. However, the expression of a potent antioxidant, heme oxygenase-1 (HO-1), was detected to a higher degree in the astrocytes ofHerpud1−/−mice than in the astrocytes ofHerpud1+/+mice 24 h after MPTP administration. Further experiments using cultured astrocytes revealed that the stress response against MPP+, an active form of MPTP, and hydrogen peroxide, both of which cause oxidative stress, was comparable between the two genotypes. These results suggest that deletion ofHerpud1may cause a slightly higher level of initial damage in the nigrastrial neurons after MPTP administration but is compensated for by higher induction of antioxidants such as HO-1 in astrocytes.

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Neural Heme Oxygenase-1 Expression in Idiopathic Parkinson's Disease

Experimental Neurology ◽

10.1006/exnr.1997.6752 ◽

1998 ◽

Vol 150 (1) ◽

pp. 60-68 ◽

Cited By ~ 204

Author(s):

H.M. Schipper ◽

A. Liberman ◽

E.G. Stopa

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Heme Oxygenase ◽

Heme Oxygenase 1 ◽

Idiopathic Parkinson’S Disease ◽

Idiopathic Parkinson's Disease

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Evaluation of salivary heme oxygenase-1 as a potential biomarker of early Parkinson's disease

Movement Disorders ◽

10.1002/mds.27328 ◽

2018 ◽

Vol 33 (4) ◽

pp. 583-591 ◽

Cited By ~ 16

Author(s):

Wei Song ◽

Vimal Kothari ◽

Ana M. Velly ◽

Marisa Cressatti ◽

Adrienne Liberman ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Heme Oxygenase ◽

Heme Oxygenase 1 ◽

Potential Biomarker ◽

Early Parkinson’S Disease

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Elevated Heme Oxygenase-1 Correlates With Increased Brain Iron Deposition Measured by Quantitative Susceptibility Mapping and Decreased Hemoglobin in Patients With Parkinson’s Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.656626 ◽

2021 ◽

Vol 13 ◽

Author(s):

Jinghui Xu ◽

Chi Xiao ◽

Weizheng Song ◽

Xiangqin Cui ◽

Mengqiu Pan ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Heme Oxygenase ◽

Human Subjects ◽

Susceptibility Mapping ◽

Iron Deposition ◽

Heme Oxygenase 1 ◽

Brain Iron ◽

Quantitative Susceptibility Mapping ◽

Brain Iron Deposition

Background: Brain iron deposition, low hemoglobin (HGB), and increased heme oxygenase-1 (HO-1) have been implicated in Parkinson’s disease (PD). However, the association among them in PD is poorly studied.Objective: To explore the association of the level of HO-1 with brain iron deposition and low level of HGB in PD.Methods: A total of 32 patients with PD and 26 controls were recruited for this study. C57BL/6 male mice were used in generating 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced chronic PD model. The Levels of serum HO-1 and HGB of human subjects and mice were assayed by ELISA, blood routine test, respectively. Quantitative susceptibility mapping (QSM) was used to quantitatively analyze brain iron deposition in human subjects and mice. HO-1 inhibitor (Sn-protoporphyrin, SnPP) was used to suppress the function and expression of HO-1 in PD mice. Correlations between the concentration of serum HO-1 and iron deposition of the region of interests (ROIs), levels of HGB, between the three factors mentioned above, and scores of clinical scales were explored in PD patients.Results: This study revealed significant elevation of the serum HO-1 concentration, iron deposition within bilateral substantial nigra (SN), red nucleus (RN), and putamen (PUT) and decrease of HGB level in PD patients. There was a significantly positive correlation between the serum HO-1 concentration and iron deposition within SN, an inverse correlation between the serum HO-1 concentration and HGB level in PD patients. A significant increase in HO-1 expression of serum and iron deposition in SN was also observed in the PD mouse model, and the SnPP could significantly reduce iron deposition in the SN.Conclusions: The high level of HO-1 may be the common mechanism of iron deposition and low HGB in PD. Therefore, the findings presented in this study indicate that HO-1 correlates with brain iron deposition and anemia in PD.

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Curcumin Protects an SH-SY5Y Cell Model of Parkinson’s Disease Against Toxic Injury by Regulating HSP90

Cellular Physiology and Biochemistry ◽

10.1159/000495326 ◽

2018 ◽

Vol 51 (2) ◽

pp. 681-691 ◽

Cited By ~ 13

Author(s):

Qiuling Sang ◽

Xiaoyang Liu ◽

Libo Wang ◽

Ling Qi ◽

Wenping Sun ◽

...

Keyword(s):

Parkinson’S Disease ◽

Cell Proliferation ◽

Parkinson's Disease ◽

Cell Model ◽

B Cell Lymphoma ◽

Underlying Mechanism ◽

Protective Role ◽

Enzyme Linked Immunosorbent Assay ◽

Western Blot Assay ◽

The Impact

Background/Aims: We aimed to explore the protective role of curcumin (Cur) in a cell model of Parkinson’s disease (PD) and its underlying mechanism. Methods: In this study, genes concerned with PD-related keywords were screened within DiGSeE database. The association network between Cur and selected genes was downloaded from STITCH, with the interactions analyzed by STRING. We built a mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+)-induced SH-SY5Y cell model of PD. Cell morphology was observed under an electron microscope. MTT assay was applied to detect cell proliferation rate. Western blot assay was conducted to determine the level of apoptotic markers, including cleaved caspase 3, Bcl-2-associated X protein (Bax) and B-cell lymphoma-extra-large (Bcl-xl). Tyrosine hydroxylase (TH), dopamine transporter (DAT) protein levels and dopamine (DA) concentration were identified as dopaminergic neuron markers and measured by western blotting or Enzyme-linked immunosorbent assay (ELISA). Results: Cur rescued the toxicity effects of MPP+ on SH-SY5Y cells, by controlling morphological change, promoting cell proliferation and inhibiting apoptosis. Of all PD-related genes, HSP90 played an important role in Cur-gene network. HSP90 protein level was elevated by MPP+, whereas Cur could reverse this effect. Silencing of HSP90 significantly attenuated the curative effect introduced by Cur, while HSP90 overexpression enhanced the impact of Cur on PD. Conclusion: Cur can effectively inhibit the toxic effect of MPP+ on SH-SY5Y cells and significantly reduce the adverse effects of MPP+ on dopaminergic neurons via up-regulation of HSP90.

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