Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mechanisms responsible for the pathological deposition of redox-active brain iron in human neurological disorders remain incompletely understood. Heme oxygenase-1 (HO-1) is a 32-kDa stress protein that degrades heme to biliverdin, free iron, and carbon monoxide. In this chapter, we review evidence that (1) HO-1 is overexpressed in CNS tissues affected by Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and other degenerative and nondegenerative CNS diseases; (2) the pro-oxidant effects of dopamine, hydrogen peroxide, beta-amyloid, and proinflammatory cytokines stimulate HO-1 expression in some of these conditions; and (3) upregulation of HO-1 in astrocytes exacerbates intracellular oxidative stress and promotes sequestration of nontransferrin-derived iron by the mitochondrial compartment. A model is presented implicating glial HO-1 induction as a "final common pathway" leading to pathological iron sequestration and mitochondrial insufficiency in a host of human CNS disorders.
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PMID:Heme oxygenase-1: transducer of pathological brain iron sequestration under oxidative stress. 1510 57

Nitric oxide and other reactive nitrogen species appear to play crucial roles in the brain such as neuromodulation, neurotransmission and synaptic plasticity, but are also involved in pathological processes such as neurodegeneration and neuroinflammation. Acute and chronic inflammation result in increased nitrogen monoxide formation and nitrosative stress. It is now well documented that NO and its toxic metabolite, peroxynitrite, can inhibit components of the mitochondrial respiratory chain leading to cellular energy deficiency and, eventually, to cell death. Within the brain, the susceptibility of different brain cell types to NO and peroxynitrite exposure may be dependent on factors such as the intracellular reduced glutathione and cellular stress resistance signal pathways. Thus neurons, in contrast to astrocytes, appear particularly vulnerable to the effect of nitrosative stress. Evidence is now available to support this scenario for neurological disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis and Huntington's disease, but also in the brain damage following ischemia and reperfusion, Down's syndrome and mitochondrial encephalopathies. To survive different types of injuries, brain cells have evolved integrated responses, the so-called longevity assurance processes, composed of several genes termed vitagenes and including, among others, members of the HSP system, such as HSP70 and HSP32, to detect and control diverse forms of stress. In particular, HSP32, also known as heme oxygenase-1 (HO-1), has received considerable attention, as it has been recently demonstrated that HO-1 induction, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. Increasing evidence suggests that the HO-1 gene is redox-regulated and its expression appears closely related to conditions of oxidative and nitrosative stress. An amount of experimental evidence indicates that increased rate of free radical generation and decreased efficiency of the reparative/degradative mechanisms, such as proteolysis, are factors that primarily contribute to age-related elevation in the level of oxidative stress and brain damage. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing such a response. These findings have led to new perspectives in medicine and pharmacology, as molecules inducing this defense mechanism appear to be possible candidates for novel, cytoprotective strategies. Particularly, manipulation of endogenous cellular defense mechanisms such as the heat shock response, through nutritional antioxidants or pharmacological compounds, represents an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration. Consistent with this notion, maintenance or recovery of the activity of vitagenes may possibly delay the aging process and decrease the occurrence of age-related diseases with resulting prolongation of a healthy life span.
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PMID:Nitric oxide and cellular stress response in brain aging and neurodegenerative disorders: the role of vitagenes. 1534 Nov 81

In the normal mammalian CNS, heme oxygenase-2 (HO-2) is constitutively, abundantly, and fairly ubiquitously expressed, whereas heme oxygenase-1 (HO-1) mRNA and protein are confined to small populations of scattered neurons and neuroglia. Unlike ho-2, the ho-1 gene in neural (and many systemic) tissues is exquisitely sensitive to upregulation by a host of pro-oxidant and other noxious stimuli. In Alzheimer disease, HO-1 immunoreactivity is significantly augmented in neurons and astrocytes of the hippocampus and cerebral cortex relative to age-matched, nondemented controls and colocalizes to senile plaques, neurofibrillary tangles, and corpora amylacea. In Parkinson disease, HO-1 decorates Lewy bodies of affected dopaminergic neurons and is highly overexpressed in astrocytes residing within the substantia nigra. The ho-1 gene is also upregulated in glial cells within multiple sclerosis plaques; in the vicinity of human cerebral infarcts, hemorrhages, and contusions; and in various other degenerative and nondegenerative human CNS disorders. The products of the heme oxygenase reaction, free ferrous iron, carbon monoxide, and biliverdin/bilirubin, are all biologically active molecules that may profoundly influence tissue redox homeostasis under a wide range of pathophysiological conditions. Evidence adduced from whole animal and in vitro studies indicates that enhanced HO-1 activity may either ameliorate or exacerbate neural injury, effects likely contingent upon the specific model employed, the duration and intensity of HO-1 induction, and the chemistry of the local redox microenvironment. HO-1 hyperactivity also promotes mitochondrial sequestration of nontransferrin iron in oxidatively challenged astroglia and may thereby contribute to the pathological iron deposition and bioenergetic failure amply documented in aging and degenerating human neural tissues.
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PMID:Heme oxygenase expression in human central nervous system disorders. 1554 18

There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia (FRDA), multiple sclerosis and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) associated with mitochondrial dysfunction. The mitochondrial genome may play an essential role in the pathogenesis of these diseases, and evidence for mitochondria being a site of damage in neurodegenerative disorders is based in part on observed decreases in the respiratory chain complex activities in Parkinson's, Alzheimer's, and Huntington's disease. Such defects in respiratory complex activities, possibly associated with oxidant/antioxidant imbalance, are thought to underlie defects in energy metabolism and induce cellular degeneration. The precise sequence of events in FRDA pathogenesis is uncertain. The impaired intramitochondrial metabolism with increased free iron levels and a defective mitochondrial respiratory chain, associated with increased free radical generation and oxidative damage, may be considered possible mechanisms that compromise cell viability. Recent evidence suggests that frataxin might detoxify ROS via activation of glutathione peroxidase and elevation of thiols, and in addition, that decreased expression of frataxin protein is associated with FRDA. Many approaches have been undertaken to understand FRDA, but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. However, increasing evidence indicates that factors such as oxidative stress and disturbed protein metabolism and their interaction in a vicious cycle are central to FRDA pathogenesis. Brains of FRDA patients undergo many changes, such as disruption of protein synthesis and degradation, classically associated with the heat shock response, which is one form of stress response. Heat shock proteins are proteins serving as molecular chaperones involved in the protection of cells from various forms of stress. In the central nervous system, heat shock protein (HSP) synthesis is induced not only after hyperthermia, but also following alterations in the intracellular redox environment. The major neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Huntington's disease (HD) and FRDA are all associated with the presence of abnormal proteins. Among the various HSPs, HSP32, also known as heme oxygenase I (HO-1), has received considerable attention, as it has been recently demonstrated that HO-1 induction, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. This may open up new perspectives in medicine, as molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. In particular, manipulation of endogenous cellular defense mechanisms, such as the heat shock response, through nutritional antioxidants, pharmacological compounds or gene transduction, may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration.
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PMID:Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia. 1589 10

Glial heme oxygenase-1 is over-expressed in the CNS of subjects with Alzheimer disease (AD), Parkinson disease (PD) and multiple sclerosis (MS). Up-regulation of HO-1 in rat astroglia has been shown to facilitate iron sequestration by the mitochondrial compartment. To determine whether HO-1 induction promotes mitochondrial oxidative stress, assays for 8-epiPGF(2alpha) (ELISA), protein carbonyls (ELISA) and 8-OHdG (HPLC-EC) were used to quantify oxidative damage to lipids, proteins, and nucleic acids, respectively, in mitochondrial fractions and whole-cell compartments derived from cultured rat astroglia engineered to over-express human (h) HO-1 by transient transfection. Cell viability was assessed by trypan blue exclusion and the MTT assay, and cell proliferation was determined by [3H] thymidine incorporation and total cell counts. In rat astrocytes, hHO-1 over-expression (x 3 days) resulted in significant oxidative damage to mitochondrial lipids, proteins, and nucleic acids, partial growth arrest, and increased cell death. These effects were attenuated by incubation with 1 microM tin mesoporphyrin, a competitive HO inhibitor, or the iron chelator, deferoxamine. Up-regulation of HO-1 engenders oxidative mitochondrial injury in cultured rat astroglia. Heme-derived ferrous iron and carbon monoxide (CO) may mediate the oxidative modification of mitochondrial lipids, proteins and nucleic acids in these cells. Glial HO-1 hyperactivity may contribute to cellular oxidative stress, pathological iron deposition, and bioenergetic failure characteristic of degenerating and inflamed neural tissues and may constitute a rational target for therapeutic intervention in these conditions.
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PMID:Over-expression of heme oxygenase-1 promotes oxidative mitochondrial damage in rat astroglia. 1622 6

The mechanisms responsible for the progressive degeneration of dopaminergic neurons and pathologic iron deposition in the substantia nigra pars compacta of patients with Parkinson's disease (PD) remain unclear. Heme oxygenase-1 (HO-1), the rate-limiting enzyme in the oxidative degradation of heme to ferrous iron, carbon monoxide, and biliverdin, is upregulated in affected PD astroglia and may contribute to abnormal mitochondrial iron sequestration in these cells. To determine whether glial HO-1 hyper-expression is toxic to neuronal compartments, we co-cultured dopaminergic PC12 cells atop monolayers of human (h) HO-1 transfected, sham-transfected, or non-transfected primary rat astroglia. We observed that PC12 cells grown atop hHO-1 transfected astrocytes, but not the astroglia themselves, were significantly more susceptible to dopamine (1 microM) + H(2)O(2) (1 microM)-induced death (assessed by nuclear ethidium monoazide bromide staining and anti-tyrosine hydroxylase immunofluorescence microscopy) relative to control preparations. In the experimental group, PC12 cell death was attenuated significantly by the administration of the HO inhibitor, SnMP (1.5 microM), the antioxidant, ascorbate (200 microM), or the iron chelators, deferoxamine (400 microM), and phenanthroline (100 microM). Exposure to conditioned media derived from HO-1 transfected astrocytes also augmented PC12 cell killing in response to dopamine (1 microM) + H(2)O(2) (1 microM) relative to control media. In PD brain, overexpression of HO-1 in nigral astroglia and accompanying iron liberation may facilitate the bioactivation of dopamine to neurotoxic free radical intermediates and predispose nearby neuronal constituents to oxidative damage.
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PMID:Astroglia overexpressing heme oxygenase-1 predispose co-cultured PC12 cells to oxidative injury. 1752 19

Physical rehabilitation with endurance exercise for patients with Parkinson's disease has not been well established, although some clinical and laboratory reports suggest that exercise may produce a neuroprotective effect and restore dopaminergic and motor functions. In this study, we used a chronic mouse model of Parkinsonism, which was induced by injecting male C57BL/6 mice with 10 doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (25 mg/kg) and probenecid (250 mg/kg) over 5 weeks. This chronic parkinsonian model displays a severe and persistent loss of nigrostriatal neurons, resulting in robust dopamine depletion and locomotor impairment in mice. Following the induction of Parkinsonism, these mice were able to sustain an exercise training program on a motorized rodent treadmill at a speed of 18 m/min, 0 degrees of inclination, 40 min/day, 5 days/week for 4 weeks. At the end of exercise training, we examined and compared their cardiorespiratory capacity, behavior, and neurochemical changes with that of the probenecid-treated control and sedentary parkinsonian mice. The resting heart rate after 4 weeks of exercise in the chronic parkinsonian mice was significantly lower than the rate before exercise, whereas the resting heart rate at the beginning and 4 weeks afterward in the control or sedentary parkinsonian mice was unchanged. Exercised parkinsonian mice also recovered from elevated electrocardiogram R-wave amplitude that was detected in the parkinsonian mice without exercise for 4 weeks. The values of oxygen consumption, carbon dioxide production, and body heat generation in the exercised parkinsonian mice before and during the Bruce maximal exercise challenge test were all significantly lower than that of their sedentary counterparts. Furthermore, the exercised parkinsonian mice demonstrated a greater mass in the left ventricle of the heart and an increased level of citrate synthase activity in the skeletal muscles. The amphetamine-induced, dopamine release-dependent locomotor activity was markedly inhibited in the sedentary parkinsonian mice and was also inhibited in the exercised parkinsonian mice. Finally, neuronal recovery from the loss of nigrostriatal tyrosine hydroxylase expression and dopamine levels in the severe parkinsonian mice after exercise was not evident. Taken all together, these data suggest that 4 weeks of treadmill exercise promoted physical endurance, resulting in cardiorespiratory and metabolic adaptations in the chronic parkinsonian mice with severe neurodegeneration without demonstrating a restorative potential for the nigrostriatal dopaminergic function.
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PMID:Endurance exercise promotes cardiorespiratory rehabilitation without neurorestoration in the chronic mouse model of parkinsonism with severe neurodegeneration. 1786 32

Proteosomal degradation of proteins is one of the major mechanisms of intracellular protein turnover. Failure of the proteosome to degrade misfolded protein is implicated in the accumulation of alpha-synuclein in Parkinson's disease (PD). Heme oxygenase-1 (HO-1), an enzyme that converts heme to free iron, carbon monoxide (CO) and biliverdin (bilirubin precursor) is expressed in response to various stressors. HO-1 is up-regulated in PD- and Alzheimer's disease-affected neural tissues. In this study, we found that HO-1 over-expression engenders dose-dependent decreases in alpha-synuclein protein levels in human neuroblastoma M17 cells. When over-expression of HO-1 was silenced in HO-1 transfected cells, level of alpha-synuclein was restored. Likewise, treatment of HO-1 over-expressing cells with the HO-1 inhibitor, tin mesoporphyrin, the iron chelator deferoxamine or antagonist of CO-dependent cGMP activation, methylene blue, mitigated the HO-1-induced reduction in alpha-synuclein levels. Furthermore, when HO-1 over-expressing cells were treated with the proteosome inhibitors, lactacystin and MG132, level of alpha-synuclein was almost completely restored. In contrast to the effect on alpha-synuclein [wild-type (WT)] levels, HO-1 over-expression did not significantly impact PD-associated alpha-synuclein (A30P) levels in these cells. HO-1 also significantly reduced aggregation of alpha-synuclein (WT) but not that of A30P. Our results suggest that HO-1, which is expressed when neurons are exposed to toxic stimuli capable of inducing protein misfolding, triggers proteosomal degradation of proteins and prevents intracellular accumulation of protein aggregates and inclusions. Resistance to HO-1 induced proteosomal degradation may render the familial PD-associated A30P mutation prone to toxic intracellular aggregation.
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PMID:The Parkinson disease-associated A30P mutation stabilizes alpha-synuclein against proteasomal degradation triggered by heme oxygenase-1 over-expression in human neuroblastoma cells. 1945 84

Postmortem studies have shown that heme oxygenase-1 (HO-1) immunoreactivity is increased in patients with Parkinson disease. HO-1 expression is highly upregulated by a variety of stress. Since the proteasome activity is decreased in patients with Parkinson disease, we investigated whether proteasome activity regulates HO-1 content. MG-132, a proteasome inhibitor, increased the amount of HO-1 protein mainly in astrocytes of primary mesencephalic cultures. Quantitative RT-PCR analysis revealed that lactacystin upregulated HO-1 mRNA expression. Proteasome inhibition with MG132 also increased the cytomegalovirus promoter-driven expression of Flag-HO-1 protein and resulted in an accumulation of ubiquitinated Flag-HO-1 in Flag-HO-1-overexpressing PC12 cells. In addition, a cycloheximide chase assay demonstrated that the degradation of Flag-HO-1 protein was slowed by MG-132. Next, the function of HO-1 which was upregulated by proteasome inhibitors was examined. Proteasome inhibitors protected dopaminergic neurons from 6-hydroxydopamine (6-OHDA)-induced toxicity and this neuroprotection was abrogated by co-treatment with zinc protoporphyrin IX, a HO-1 inhibitor. Furthermore, 6-OHDA-induced toxicity was blocked by bilirubin and carbon monoxide, products of the HO-1-catalyzed degradation of heme. These results suggest that mesencephalic HO-1 protein level is regulated by proteasome activity and the elevation by proteasome inhibition affords neuroprotection.
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PMID:Elevation of heme oxygenase-1 by proteasome inhibition affords dopaminergic neuroprotection. 2015 7

Heme oxygenase-1 (HO-1), an enzyme degrading heme to carbon monoxide, free iron, and biliverdin, participates in the cell defence against oxidative stress and it has been speculated that it might be a new therapeutic target for neuroprotection. In this review, we discuss recent findings on the regulation of the HO-1 gene, Hmox1, in the brain with particular focus on the transcription factors Nrf2 and HIF-1. Functional polymorphisms in Hmox1 have been associated with high risk for Alzheimer's and Parkinson's disease. Hence, we review the current knowledge on the role of HO-1 and its enzymatic products on these two pathologies as well as ischemic brain injury. HO-1 modulates the inflammatory response in several scenarios, and therefore we discuss its role in modulation of the innate immune cell of the brain, microglia. From the therapeutic side, the blood brain barrier represents an obstacle to directly modulate heme oxygenase activity, but drugs activating the transcription actor Nrf2, which have a very diverse molecular structure, may be good candidates to induce HO-1 in concert with other antioxidant and detoxification enzymes. A more complete understanding on the mechanisms regulating HO-1 expression in brain cells and how these mechanisms are involved in neuropathological changes will be essential to develop these new therapeutic approaches.
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PMID:Targeting heme oxygenase-1 for neuroprotection and neuroinflammation in neurodegenerative diseases. 2070 49


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