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

Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder. Mutations in the PINK1 gene are linked to the autosomal recessive early onset familial form of PD. The physiological function of PINK1 and pathological abnormality of PD-associated PINK1 mutants are largely unknown. We here show that inactivation of Drosophila PINK1 (dPINK1) using RNAi results in progressive loss of dopaminergic neurons and in ommatidial degeneration of the compound eye, which is rescued by expression of human PINK1 (hPINK1). Expression of human SOD1 suppresses neurodegeneration induced by dPINK1 inactivation. Moreover, treatment of dPINK1 RNAi flies with the antioxidants SOD and vitamin E significantly inhibits ommatidial degeneration. Thus, dPINK1 plays an essential role in maintaining neuronal survival by preventing neurons from undergoing oxidative stress, thereby suggesting a potential mechanism by which a reduction in PINK1 function leads to PD-associated neurodegeneration.
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PMID:Antioxidants protect PINK1-dependent dopaminergic neurons in Drosophila. 1693 56

Parkinson disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN). However, the mechanism of the pathology of PD still remains poorly understood. Because the administration of the herbicide paraquat triggers selective dopaminergic neuronal cell death, exposure of mice to this herbicide is one valuable model for studying the pathological aspects of PD. In this study, we investigated the protective effects of PEP-1-SOD in vitro and in vivo under exposure to the herbicide paraquat. The viability of neuronal cells treated with paraquat was markedly increased by transduced PEP-1-SOD. When the PEP-1-SOD fusion protein was injected intraperitoneally into mice, a completely protective effect against dopaminergic neuronal cell death in the SN was observed. This protective effect was synergistically increased when the PEP-1-SOD was cotransduced with Tat-alpha-synuclein. These results suggest that PEP-1-SOD provides a strategy for therapeutic delivery in various human diseases related to reactive oxygen species, including PD.
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PMID:PEP-1-SOD fusion protein efficiently protects against paraquat-induced dopaminergic neuron damage in a Parkinson disease mouse model. 1696 31

1-Methyl-4-phenylpyridinium ion (MPP(+)), an inhibitor of mitochondrial complex I, has been widely used as a neurotoxin because it elicits a severe Parkinson's disease-like syndrome with elevation of intracellular reactive oxygen species (ROS) level and apoptotic death. Rosiglitazone, a peroxisome proliferator-activated receptor (PPAR)-gamma agonist, has been known to show various non-hypoglycemic effects, including anti-inflammatory, anti-atherogenic, and anti-apoptotic. In the present study, we investigated the protective effects of rosiglitazone on MPP(+) induced cytotoxicity in human neuroblastoma SH-SY5Y cells, as well as underlying mechanism. Our results suggested that the protective effects of rosiglitazone on MPP(+) induced apoptosis may be ascribed to its anti-oxidative properties, anti-apoptotic activity via inducing expression of SOD and catalase and regulating the expression of Bcl-2 and Bax. These data indicated that rosiglitazone might provide a valuable therapeutic strategy for the treatment of progressive neurodegenerative disease such as Parkinson's disease.
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PMID:Rosiglitazone protects human neuroblastoma SH-SY5Y cells against MPP+ induced cytotoxicity via inhibition of mitochondrial dysfunction and ROS production. 1726 88

Emerging evidence suggests the beneficial effects of estrogen on Parkinson's disease (PD), yet the mechanisms of action implicated remain elusive. While experimental evidence suggests that estrogen possesses potent antioxidative properties, it is still unknown whether the hormone exhibits a neuroprotection in a PD animal model through its antioxidant activities. This study therefore investigated the effects of 17beta-estradiol (E2) on the immunoreactivity of nigral neurons and glia for nitrotyrosine (NT, a stable marker for oxidative stress), Cu/Zn superoxide dismutase (SOD1) and Mn superoxide dismutase (SOD2) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. Adult male mice were treated with E2 or vehicle for 11 days during which they were injected with MPTP or saline on the sixth day. The brains were collected on day 11 and quantitative immunohistochemistry was used to assess the number of NT-, SOD1- and SOD2-immunoreactive (IR) cells in the substantia nigra pars compacta (SNpc). In saline-treated group, E2 decreased NT-IR neuronal number and raised SOD1 and SOD2 expression in neurons and glia in the SNpc. MPTP induced a significant increase in the number of NT- and SOD2-IR neurons, but decreased the number of SOD1-IR neurons. MPTP also triggered a significant increase of SOD2- and SOD1-IR glial number. E2 pretreatment in MPTP mice reduced the number of NT-IR neurons, increased the number of SOD1- and SOD2-IR neurons, but did not alter the MPTP effect on glia immunoreactive to either SOD. Stimulation of SOD1 and SOD2 expression in nigral neurons suggests that E2 provides neuroprotection against MPTP-induced oxidative stress, partly through its ability to act as an antioxidant.
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PMID:17Beta-estradiol reduces nitrotyrosine immunoreactivity and increases SOD1 and SOD2 immunoreactivity in nigral neurons in male mice following MPTP insult. 1764 Jun 23

Activation of the caspase family of cysteine proteases results in the deregulation of cellular homeostasis and apoptosis. This deregulation is a key factor in the development of Alzheimer's disease, Parkinson's disease, and cancer. Thus, the caspases are important drug targets for the therapeutic intervention of a number of pathological states involving inflammation and apoptosis. In this article, we report the results of inhibition kinetics and binding studies utilizing fluorescence spectroscopy and isothermal titration calorimetry to characterize the mechanism of interaction of caspase-3 with three different classes of inhibitors: peptidomimetics, isatins, and pyrimidoindolones. The peptidomimetics and pyrimidoindolones bind to both active sites of the caspase-3 homodimer with equal affinity and favorable enthalpic and entropic binding contributions. Enzyme activity is abolished when both active sites are occupied with the above inhibitors. In contrast, the isatins bind to caspase-3 with significant heat release (-12 kcal/mol) and negative entropy. In addition, enzyme activity is abolished upon isatin binding to one active site of the homodimer resulting in half-site reactivity. Our studies provide important mechanistic insight into inhibitor interactions with caspase-3 and a way to characterize inhibitor interactions that may not be readily apparent from the crystal structure.
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PMID:Biochemical and biophysical characterization of inhibitor binding to caspase-3 reveals induced asymmetry. 1764 76

Oxidative stress is widely recognized as a key mediator of degenerative processes in Parkinson's disease (PD). Recently, we demonstrated that the dopaminergic toxin MPP+ initiates oxidative stress to cause caspase-3-dependent apoptotic cell death in mesencephalic dopaminergic neuronal (N27) cells. In this study, we determined the source of reactive oxygen species (ROS) produced during MPP+-induced apoptotic cell death. In addition to mitochondria, plasma membrane NADPH oxidase is considered a major producer of ROS inside the cell. Here, we show that N27 neuronal cells express key NADPH oxidase subunits gp91phox and p67phox. We used structurally diverse NADPH oxidase inhibitors, aminoethyl-benzenesulfonylfluoride (AEBSF, 100-1000microM), apocynin (100-1000microM), and diphenylene iodonium (DPI, 3-30microM), to inhibit intrinsic NADPH oxidase activity in N27 cells. Flow cytometric analysis using the ROS-sensitive dye hydroethidine revealed that AEBSF blocked 300microM MPP+-induced ROS production for over 45min in N27 cells, in a dose-dependent manner. Further treatment with DPI, apocynin, and SOD also blocked MPP+-induced ROS production. In Sytox cell death assays, co-treatment with AEBSF, apocynin, or DPI for 24h significantly suppressed MPP+-induced cytotoxic cell death. Similarly, co-treatment with these inhibitors also significantly attenuated MPP+-induced increases in caspase-3 enzymatic activity. Furthermore, quantitative DNA fragmentation ELISA assays revealed that AEBSF, DPI, and apocynin rescue N27 cells from MPP+-induced apoptotic cell death. Together, these results indicate for the first time that intracellular ROS generated by NAPDH oxidase are present within the mesencephalic neuronal cells, and are a key determinant of MPP+-mediated dopaminergic degeneration in in vitro models of dopaminergic degeneration. This study supports a critical role of NADPH oxidase in the oxidative damage in PD; targeting this enzyme may lead to novel therapies for PD.
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PMID:Pharmacological inhibition of neuronal NADPH oxidase protects against 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress and apoptosis in mesencephalic dopaminergic neuronal cells. 1790 25

The flavoprotein D-amino acid oxidase (DAO) degrades the gliotransmitter D-Ser, a potent activator of N-methyl-D-aspartate-type glutamate receptors. A body of evidence suggests that DAO, together with its activator, G72 protein, may play a key role in the pathophysiology of schizophrenia. It has also been suggested that 3,4-dihydroxy-D-phenylalanine (D-DOPA), the stereoisomer of 3,4-dihydroxy-L-phenylalanine (L-DOPA), is oxidized by DAO and converted to dopamine via an alternative biosynthetic pathway. We determined the crystal structures of human DAO in complex with the reaction products of two clinically important substrates, D-Ser and D-DOPA. Kinetic data show that the maximum velocity is much greater for D-DOPA than that for D-Ser, which strongly supports the proposed alternative pathway for dopamine biosynthesis in the treatment of Parkinson's disease. In addition, biochemical characterization of human DAO indicates that it binds FAD more weakly than does porcine D-amino acid oxidase (pDAO) and exists as a stable homodimer, even in the apoprotein form. Determination of the structures of human DAO in various states reveals that, in contrast to pDAO, the hydrophobic-Val-Ala-Ala-Gly-Leu (VAAGL) stretch (residues 47-51, structurally ambivalent peptide) located at the si-face of the flavin ring assumes a uniquely stable conformation, which provides a structural basis for the unique kinetic features of human DAO.
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PMID:Human D-amino acid oxidase: an update and review. 1792 43

We discovered the gene for young onset autosomal recessive parkinsonism in 1998. We were gifted two lucky episodes. This is a short history on how we were able to discover the gene in a short period. We were primarily interested in the pathogenesis of sporadic Parkinson's disease (PD). We decided to do a genetic association study using a polymorphism of manganese superoxide dismutase (Mn SOD), as it is located at the pivotal position of oxidative stress and mitochondria. While we were screening many patients, we encountered what appeared to be young onset autosomal recessive family, which appeared to be linked to the sod2 locus, which had been mapped to the long arm of chromosome 6. We did linkage analysis on 13 similar families and obtained lod score above 9. Another fortune was that while doing linkage analysis, we encountered a patient who showed complete absence of one of the microsatellite markers that we were using in the linkage analysis. We thought that the marker was likely to be located within the disease gene. We started molecular cloning using this marker as the initial probe. Eventually we were able to clone a novel gene, which we named as parkin.
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PMID:[Discovery of the parkin gene; the gene for young onset autosomal recessive parkinsonism (AR)]. 1821 Jul 91

Neuronal nicotinic acetylcholine receptors (nAChRs) are important therapeutic targets for various diseases, including Alzheimer's disease, Parkinson's disease, and schizophrenia, as well as for cessation of smoking. Based on the recently determined crystal structure of the extracellular domain (ECD) of the mouse nAChR alpha1 subunit complexed with alpha-bungarotoxin at 1.94A resolution, we have constructed three-dimensional models of the ECD of the monomer, homodimer, and homopentamer of the human alpha7 nAChR and investigated in detail the interface between the two alpha7 subunits. The docking of the agonist in the ligand-binding pocket of the human alpha7 dimer was also performed and found consistent with results from labeling and mutagenesis experiments. Since the nAChR ligand-binding site is a useful target for mutagenesis studies and the rational design of drugs against diseases, these models provide useful information for future work.
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PMID:Model of the extracellular domain of the human alpha7 nAChR based on the crystal structure of the mouse alpha1 nAChR extracellular domain. 1832 5

The addition of the neuropeptide carnosine (beta-alanyl-L-histidine) as a food additive to the basic protocol of Parkinson's disease treatment results in significant improvement of neurological symptoms, along with increase in red blood cell Cu/Zn-SOD and decrease in blood plasma protein carbonyls and lipid hydroperoxides, with no noticeable change in platelets MAO B activity. The combination of carnosine with basic therapy may be a useful way to increase efficiency of PD treatment.
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PMID:Carnosine [corrected] increases efficiency of DOPA therapy of Parkinson's disease: a pilot study. 1872 14


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