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)

There is growing evidence that oxidative stress and mitochondrial respiratory failure with attendant decrease in energy output are implicated in nigral neuronal death in Parkinson disease (PD). It is not known, however, which cellular elements (neurons or glial cells) are major targets of oxygen-mediated damage. 4-Hydroxy-2-nonenal (HNE) was shown earlier to react with proteins to form stable adducts that can be used as markers of oxidative stress-induced cellular damage. We report here results of immunochemical studies using polyclonal antibodies directed against HNE-protein conjugates to label the site of oxidative damage in control subjects (ages 18-99 years) and seven patients that died of PD (ages 57-78 years). All the nigral melanized neurons in one of the midbrain sections were counted and classified into three groups according to the intensity of immunostaining for HNE-modified proteins--i.e., no staining, weak staining, and intensely positive staining. On average, 58% of nigral neurons were positively stained for HNE-modified proteins in PD; in contrast only 9% of nigral neurons were positive in the control subjects; the difference was statistically significant (Mann-Whitney U test; P < 0.01). In contrast to the substantia nigra, the oculomotor neurons in the same midbrain sections showed no or only weak staining for HNE-modified proteins in both PD and control subjects; young control subjects did not show any immunostaining; however, aged control subjects showed weak staining in the oculomotor nucleus, suggesting age-related accumulation of HNE-modified proteins in the neuron. Our results indicate the presence of oxidative stress within nigral neurons in PD, and this oxidative stress may contribute to nigral cell death.
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PMID:Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease. 861 Jan 3

Accumulation of various mutations in the mitochondrial genome is proposed as an important contributor to aging and degenerative diseases. Extensive fragmentation of mtDNA was detected in association with increased 8-hydroxydeoxyguanosine content in the heart mitochondrial DNA (mtDNA) from a patient with premature aging and mitochondrial cardiomyopathy, who carried a mutation within the mitochondrial tRNA(Asp) gene. This result suggests that damage to mtDNA by hydroxyl radical and accumulation of deleted mtDNA can be accelerated by a specific mitochondrial genotype. Similarly, extensive fragmentation of mtDNA was also detected in cultured cells exposed to a high oxygen concentration atmosphere, implying that mtDNA is vulnerable to reactive oxygen species. To clarify the role of point mutations accumulated in mtDNA, we examined the sequence heterogeneity of mtDNA in the skeletal muscle of a MELAS patient who carried a mutation within the mitochondrial tRNA(leu)(UUR) gene. The analysis revealed that the frequency of mutant clones in the MELAS muscle was significantly higher than those in an age-matched control muscle and a control placenta. Some of these nucleotide substitutions were missense and nonsense mutations, which potentially have deleterious effects on the mitochondrial function. The frequency of nucleotide substitutions in the striatum of three patients with Parkinson's disease was also significantly higher than that in control tissues. We also observed increased protein modification by 4-hydroxy-2-nonenal, a lipid peroxidation by-product, in Parkinson's disease. These results suggests that a vicious cycle contributes to the progression of degenerative process. In this cycle, first a primary mitochondrial mutation(s) induces a mitochondrial respiratory defect, which increases the leakage of reactive oxygen species (ROS) from the respiratory chain. Then the ROS would trigger accumulation of secondary mtDNA mutations in postmitotic cells, leading to further aggravation of mitochondrial respiratory defects and increased production of ROS and lipid peroxides from mitochondria, and thus resulting in degeneration of cellular components.
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PMID:Accumulation of deletions and point mutations in mitochondrial genome in degenerative diseases. 868 11

(E)-4-Hydroxy-2-nonenal (HNE) is a highly reactive product of the free radical-stimulated lipid peroxidation of phospholipid-bound arachidonic acid in cellular membranes. We describe a sensitive and specific method for the determination of HNE in clinical samples. The method is based on the formation of the O-pentafluorobenzyl (O-PFB) oxime derivative of HNE, which is then extracted and cleaned up by solid-phase extraction. The HNE O-PFB oxime is then analysed without further derivatisation by capillary column gas chromatography-negative ion chemical ionisation mass spectrometry (GC-NICI-MS) using selected-ion monitoring. Concentrations down to the pmol range were achieved using deuterated HNE as an internal standard. The method was used to determine HNE in the cerebrospinal fluid and plasma of patients with Parkinson's disease, the plasma of patients with HIV-1 infection and AIDS and in inflamed mucosal biopsy specimens from patients with inflammatory bowel disease.
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PMID:Determination of the lipid peroxidation product (E)-4-hydroxy-2-nonenal in clinical samples by gas chromatography--negative-ion chemical ionisation mass spectrometry of the O-pentafluorobenzyl oxime. 917 61

Increasing age and inheritance of the epsilon 4 allele of apolipoprotein E (APOE4) are significant risk factors for sporadic and late onset familial Alzheimer disease (AD); however, the mechanisms by which either leads to AD are unknown. Numerous studies have associated advancing age with increased indices of oxidative challenge to brain, and with still further increased oxidative damage to relevant brain regions in AD patients. A major consequence of oxidative damage to brain is lipid peroxidation with production of the neurotoxic metabolite 4-hydroxy-2-nonenal (HNE). HNE reacts with protein to yield several adducts, including a pyrrole adduct that forms irreversibly in biological systems. Previously, we have shown in a small number of AD and control patients that HNE pyrrole adduct antiserum is immunoreactive with neurofibrillary tangles (NFT), and that this reactivity was significantly associated with inheritance of APOE4. Others have confirmed this pattern of immunoreactivity in AD brain but did not observe an association with APOE4. Herein, we have expanded the study group to 19 AD patients homozygous for APOE4 or APOE3, as well as 30 patients with other neurodegenerative diseases, including diffuse Lewy body disease, Pick's disease, progressive supranuclear palsy, Parkinson's disease, and human immunodeficiency virus-1 encephalitis. HNE pyrrole adduct immunoreactivity on NFT in AD patients was strongly associated with APOE4 homozygosity. With the exception of rare immunoreactive Pick bodies in one case of Pick's disease, no other structure was recognized by HNE pyrrole adduct antiserum in this series of patients. We propose that there is a significant difference between the interaction of apoE3 and apoE4 with lipid peroxidation in the brains of AD patients.
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PMID:4-hydroxy-2-nonenal pyrrole adducts in human neurodegenerative disease. 925 56

(E)-4-hydroxy-2-nonenal (HNE) is a toxic end-product of the free radical-stimulated peroxidation of phospholoipid-bound arachidonic acid in cell membranes. There is a growing body of evidence to suggest that free radicals may play an important role in the pathology of Parkinson's disease. HNE is highly electrophilic and is conjugated to reduced glutathione (GSH) by glutathione S-transferase. The depletion of GSH in the substantia nigra of Parkinson's patients and in the brainstem of mice treated with the neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) prompted this study on the concentrations of HNE in the cerebrospinal fluid (CSF) and plasma of Parkinson's patients and the brainstem of mice treated with MPTP. HNE was identified and quantitated by a highly specific and sensitive method based on the gas chromatography-negative-ion chemical ionisation mass spectrometry of the O-pentafluorobenzyl oxime derivative using 9D3-4-hydroxy-2-nonenal as an internal standard. The mean concentration of HNE in the CSF of patients with Parkinson's disease was 1.47+/-0.76 microM (mean+/-SD, n=10), while the concentration in the CSF of a group of control patients was 0.38+/-0.14 microM (n=10; p < .01). The mean concentration of HNE in the plasma of Parkinson's patients was 0.68+/-0.15 microM (n=20) and the concentration in the control group was 0.47+/-0 12 microM (n=20; p < .05). The mean peak concentration of HNE in the brainstem of mice after a single s.c. dose of MPTP (40 mg/kg) was 3.62+/-0.36 nM/g wet wt. (n=17) at 12 h while the control value was 0.45+/-0.05 nM/g wet wt. (n=20; p < .05). The GSH concentration in the brainstem of MPTP-treated mice at 24 h. was 0.65+/-0.03 microM/g wet wt. (n=14) and the control value was 1.25+/-0.03 microM/g wet wt. (n=20; p < .01). The corresponding concentration of GSH-HNE-conjugate at 24 h was 0.32+/-0.09 microM/g wet wt. (n=12) compared with a control value of 0.05+/-0.02 (n=16; p < .01). After treatment with alpha-tocopherol (2.35 g/kg s.c. daily x 3) the mean concentration of HNE 12 hr. after MPTP injection was 0.89+/-0.06 nM/g wet wt. (n=18). The HNE concentration in a group not treated with alpha-tocopherol prior to MPTP injection was 3.49+/-0.09 nM/g wet wt. (n=14; p < .05). The concentration of GSH in the mice pretreated with alpha-tocopherol before MPTP injection was 1.14+/-0.02 microM/g wet wt. (n=17) at 24 h compared to 0.61+/-0.02 microM/g wet wt. (n=14) in the untreated mice (p < .05). The direct injection of HNE (1, 10, 100, 1,000 microM) into the substantia nigra caused a dose dependent depletion of GSH in the brainstem of mice. The mean concentration of GSH 24 hr after the injection of 100 microM of HNE was 0.43+/-0.22 microM/g wet wt. (n=4) compared with a control value of 1.48+/-0.02 microM/g wet wt. (n=8; p < .05). The corresponding concentration of GSH-HNE-conjugate was 0.32+/-0.12 microM/g wet wt. (n=4) while the control value was 0.04+/-0.02 microM/g wet wt. (n=8). These data suggest that HNE may be a causative neurotoxin in Parkinson's disease and that HNE may also be involved in MPTP toxicity.
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PMID:(E)-4-hydroxy-2-nonenal may be involved in the pathogenesis of Parkinson's disease. 966 92

Multiple lines of evidence indicate that oxidative stress is a critical pathogenic factor in Parkinson disease (PD) and diffuse Lewy body disease (DLBD). Previously, we demonstrated increased levels of redox-active iron in Lewy bodies, and that Lewy bodies accumulate advanced glycation end-products. To further characterize the role of oxidative stress in diseases with Lewy body formation, we examined immunocytochemically eight cases of PD and five cases of DLBD for adducts of the lipid peroxidation adduct 4-hydroxy-2-nonenal, and for N(epsilon)-(carboxymethyl)lysine (CML). Our findings demonstrate immunolocalization of 4-hydroxynonenal and CML to Lewy bodies in PD and DLBD. These findings not only support prior studies indicating that lipid peroxidation is increased in patients with PD and DLBD but that oxidative damage may play a critical role in Lewy body formation.
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PMID:Hydroxynonenal adducts indicate a role for lipid peroxidation in neocortical and brainstem Lewy bodies in humans. 1181 45

Growing evidence indicates that aldehydic products of lipid peroxidation play an important role in the pathophysiology of neurodegenerative disorders such as Parkinson's disease. In the present study, modulation of D1-like receptor binding and function by saturated alkanals and unsaturated alkenals, 4-hydroxynonenal (4-HNE) and trans-2-nonenal (nonenal), was examined in rat striatal membranes. The 4-HNE and nonenal were most effective in modulating both the specific D1-like receptor binding and function as measured by adenylate cyclase activation. Inactivation of receptor binding and the depression of adenylate cyclase activity were partially prevented by protection of the D1/D5-receptor with the agonist (R)-SKF 38393 or the specific antagonist SCH 23390. 4-HNE inhibited adenylate cyclase activation by Gpp (NH)p and forskolin, indicating the modulation of Gsalpha and the catalytic subunit of adenylate cyclase, respectively. Our data suggests that aldehydic products of lipid peroxidation can directly modulate the binding and functional properties of D1/D5 receptors, as well as effector proteins within their signaling pathway.
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PMID:Modulation of D1-like dopamine receptor function by aldehydic products of lipid peroxidation. 1264 68

Lipid peroxidation and mitochondrial dysfunction are associated with multiple neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. 4-Hydroxy-trans-2-nonenal (HNE) is a major, neurotoxic product of lipid peroxidation whose levels are elevated in these diseases. Previous data from this laboratory demonstrate that mitochondria play an important role in the detoxification of HNE particularly through the oxidation of HNE to 4-hydroxy-trans-2-nonenoate (HNEAcid). In this work, we examined the disposition of HNE when incubated with intact, well-coupled, rat brain mitochondria. Our results demonstrated that HNE loss occurred in a time- and concentration-dependent, saturable manner with a K(M) of 28.0 +/- 11.8 microM HNE and a V(Max) of 10.0 +/- 1.7 nmol/min/mg. HNEAcid formation occurred in a saturable manner with a K(M) of 25.3 +/- 6.3 microM HNE and a V(Max) of 4.4 +/- 0.43 nmol/min/mg. The formation of HNE-glutathione adducts and HNE-protein adducts comprised only a small percentage of HNE consumption. HNE metabolism was significantly diminished in rat brain mitochondria isolated from older animals. We then tested the hypothesis that the mitochondrial NADH/NAD(+) ratio regulated matrix aldehyde dehydrogenase activity. Our results demonstrate that HNE oxidation was significantly inhibited to a greater extent with pyruvate and malate as substrates vs succinate. Complex I inhibition with respiratory substrates further blocked HNE detoxification. Rotenone (100 nM) inhibited respiration by 15% whereas HNEAcid formation was decreased to 72% of control levels. These results demonstrate that in situ mitochondrial aldehyde detoxification is affected by decrements in NAD(+) availability and complex I activity.
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PMID:Metabolism of 4-hydroxy-trans-2-nonenal by central nervous system mitochondria is dependent on age and NAD+ availability. 1537 62

Systemic treatment of mice with the herbicide paraquat causes the selective loss of nigrostriatal dopaminergic neurons, reproducing the primary neurodegenerative feature of Parkinson's disease. To elucidate the role of oxidative damage in paraquat neurotoxicity, the time-course of neurodegeneration was correlated to changes in 4-hydroxy-2-nonenal (4-HNE), a lipid peroxidation marker. When mice were exposed to three weekly injections of paraquat, no nigral dopaminergic cell loss was observed after the first administration, whereas a significant reduction of neurons followed the second exposure. Changes in the number of nigral 4-HNE-positive neurons suggest a relationship between lipid peroxidation and neuronal death, since a dramatic increase in this number coincided with the onset and development of neurodegeneration after the second toxicant injection. Interestingly, the third paraquat administration did not cause any increase in 4-HNE-immunoreactive cells, nor did it produce any additional dopaminergic cell loss. Further evidence of paraquat-induced oxidative injury derives from the observation of nitrotyrosine immunoreactivity in the substantia nigra of paraquat-treated animals and from experiments with ferritin transgenic mice. These mice, which are characterized by a decreased susceptibility to oxidative stress, were completely resistant to the increase in 4-HNE-positive neurons and the cell death caused by paraquat. Thus, paraquat exposure yields a model that emphasizes the susceptibility of dopaminergic neurons to oxidative damage.
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PMID:Role of oxidative stress in paraquat-induced dopaminergic cell degeneration. 1585 6

Several lines of evidence, including an increased level of lipid peroxidation and the depletion of antioxidant molecules like as glutathione (GSH), indicate that oxidative stress plays an important role in the pathogenesis of several neurodegenerative disorders, such as Parkinson's disease (PD) and Alzheimer's disease (AD). We previously observed a significant increased level of DNA oxidative damage in peripheral blood cells of PD patients, with respect to controls, moreover, the activity of glutathione transferases (GSTs) measured in circulating plasma was higher in controls than in PD patients, suggesting a lower enzymatic protection in PD individuals. Among human GSTs, glutathione transferase A4-4 displays a high catalitic activity towards 4-hydroxy-2-nonenal (HNE), a marker of lipid peroxidation whose levels have been found significantly increased in the substantia nigra of Parkinson's disease patients, in respect to controls. We performed this study to determine the presence of allelic variants of functional interest in the coding region of the hGSTA4 gene on 60 PD patients and 60 healthy controls. By the combined effort of polymerase chain reaction/single-strand conformation polymorphisms (PCR/SSCP) techniques, we observed a single nucleotide polymorphism (SNP) G351A leading to the silent mutation Gln117Gln. No significant difference was observed in the distribution of this polymorphism between PD individuals and controls, moreover, we did not observe any other polymorphism in the hGSTA4 gene in our population. Further studies are required to test the role played by both factors regulating the level of the expression of the hGSTA4 gene and any possible post-translational modification of the protein, in the protection against oxidative damage in neuronal cells.
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PMID:Molecular implications of the human glutathione transferase A-4 gene (hGSTA4) polymorphisms in neurodegenerative diseases. 1605 70


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