Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The subthalamic nucleus (STN), a major component of the basal ganglia (BG), plays a crucial role in motor activity and cognitive functions. In current models of the BG, the STN is considered to act by activating the gamma-aminobutyric acid (GABA)ergic neurons of the BG output nuclei, thus inhibiting their thalamic and brain stem targets. However, in addition to the BG output nuclei, the STN has also been reported to innervate the cerebral cortex and the striatum. Here, the anatomo-functional organization of STN projections to the cerebral cortex was investigated using anatomical and electrophysiological approaches. First, wheatgerm agglutinin-conjugated horseradish peroxidase was injected into defined areas of the cerebral cortex to analyse the spatial distribution of retrogradely labelled STN neurons. The mode of cortical innervation by the STN was then determined using extracellular deposits of Phaseolus vulgaris-leucoagglutinin into the STN. Finally, the functional organization of the cortico-STN relationships was investigated by extracellularly recording single STN units antidromically driven from the cerebral cortex. Our results indicate that STN innervates the sensory-motor and prefrontal cortices, the densest projections terminating in cortical layers I-III of the orofacial motor area. The matching between the topographic distribution of subthalamo-cortical neurons and cortico-subthalamic projections forms the basis of a functional cortico-STN loop circuit that is partially opened. In pathological situations such as Parkinson's disease and epilepsy, the STN-cortex loop circuit might contribute to propagate pathological oscillations favouring the emergence of abnormal synchronized activities and a loss of functional selectivity in the cortico-BG network.
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PMID:Evidence for a direct subthalamo-cortical loop circuit in the rat. 1854 46

Mutations in PARK7 DJ-1 have been associated with autosomal-recessive early-onset Parkinson's disease (PD). This gene encodes for an atypical peroxiredoxin-like peroxidase that may act as a regulator of transcription and a redox-dependent chaperone. Although large gene deletions have been associated with a loss-of-function phenotype, the pathogenic mechanism of several missense mutations is less clear. By performing a yeast two-hybrid screening from a human fetal brain library, we identified TRAF and TNF receptor-associated protein (TTRAP), an ubiquitin-binding domain-containing protein, as a novel DJ-1 interactor, which was able to bind the PD-associated mutations M26I and L166P more strongly than wild type. TTRAP protected neuroblastoma cells from apoptosis induced by proteasome impairment. In these conditions, endogenous TTRAP relocalized to a detergent-insoluble fraction and formed cytoplasmic aggresome-like structures. Interestingly, both DJ-1 mutants blocked the TTRAP protective activity unmasking a c-jun N-terminal kinase (JNK)- and p38-MAPK (mitogen-activated protein kinase)-mediated apoptosis. These results suggest an active role of DJ-1 missense mutants in the control of cell death and position TTRAP as a new player in the arena of neurodegeneration.
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PMID:Aggresome-forming TTRAP mediates pro-apoptotic properties of Parkinson's disease-associated DJ-1 missense mutations. 1902 31

Damage of presynaptic mitochondria could result in release of proapoptotic factors that threaten the integrity of the entire neuron. We discovered that alpha-synuclein (Syn) forms a triple complex with anionic lipids (such as cardiolipin) and cytochrome c, which exerts a peroxidase activity. The latter catalyzes covalent hetero-oligomerization of Syn with cytochrome c into high molecular weight aggregates. Syn is a preferred substrate of this reaction and is oxidized more readily than cardiolipin, dopamine, and other phenolic substrates. Co-localization of Syn with cytochrome c was detected in aggregates formed upon proapoptotic stimulation of SH-SY5Y and HeLa cells and in dopaminergic substantia nigra neurons of rotenone-treated rats. Syn-cardiolipin exerted protection against cytochrome c-induced caspase-3 activation in a cell-free system, particularly in the presence of H(2)O(2). Direct delivery of Syn into mouse embryonic cells conferred resistance to proapoptotic caspase-3 activation. Conversely, small interfering RNA depletion of Syn in HeLa cells made them more sensitive to dopamine-induced apoptosis. In human Parkinson disease substantia nigra neurons, two-thirds of co-localized Syn-cytochrome c complexes occurred in Lewy neurites. Taken together, these results indicate that Syn may prevent execution of apoptosis in neurons through covalent hetero-oligomerization of cytochrome c. This immediate protective function of Syn is associated with the formation of the peroxidase complex representing a source of oxidative stress and postponed damage.
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PMID:Peroxidase mechanism of lipid-dependent cross-linking of synuclein with cytochrome C: protection against apoptosis versus delayed oxidative stress in Parkinson disease. 1935 80

Carbidopa and benserazide have been described as inhibitors of dopa decarboxylase and both have been used in the treatment of Parkinson's disease. Because of their chemical structure as polyphenols, these compounds can behave as substrates of tyrosinase and peroxidase. We demonstrate that these enzymes oxidize both substrates. Since o-quinones are unstable, a chronometric method for enzymatic initial rate determinations was used based on measurements of the lag period in the presence of micromolar concentrations of ascorbic acid to kinetically characterize these substrates. In the case of tyrosinase, the values of the Michaelis constant for both substrates were greater than those described for dopa, although the catalytic constants were lower, probably due to the greater size of the substitute group in carbon 1. As regards peroxidase, the saturation of the enzyme by both substrates is possible, however this effect does not occur with the isomers of dopa. The distance of the charges from the benzene ring may enable the ring to approach the iron of the active site and, therefore, act.
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PMID:Kinetic characterization of the oxidation of carbidopa and benserazide by tyrosinase and peroxidase. 1950 46

The total GSH depletion observed in the substantia nigra (SN) appears to be responsible for subsequent oxidative stress (OS), mitochondrial dysfunction, and dopaminergic cell loss in patients with Parkinson's disease. A strategy to prevent the OS of dopaminergic cells in the SN may be the use of chemopreventive agents as inducers of endogenous GSH, antioxidant and phase 2 enzymes. In this study, we demonstrated that treatment of the dopaminergic-like neuroblastoma SH-SY5Y cell line with sulforaphane (SF), a cruciferous vegetables inducer, resulted in significant increases of total GSH level, NAD(P)H : quinone oxidoreductase-1, GSH-transferase and -reductase, but not GSH-peroxidase, catalase and superoxide dismutase activities. Further, the elevation of GSH levels, GSH-transferase and NAD(P)H:quinone oxidoreductase-1 activities was correlated to an increase of the resistance of SH-SY5Y cells to toxicity induced by H(2)O(2) or 6-hydroxydopamine (6-OHDA). The pre-treatment of SH-SY5Y cells with SF was also shown to prevent various apoptotic events (mitochondrial depolarization, caspase 9 and 3 activation and DNA fragmentation) and necrosis elicited by 6-OHDA. Further, the impairment of antioxidant capacity and reactive oxygen species formation at intracellular level after exposure to 6-OHDA was effectively counteracted by pre-treatment with SF. Last, both the cytoprotective and antioxidant effects of SF were abolished by the addition of buthionine sulfoximine supporting the main role of GSH in the neuroprotective effects displayed by SF. These findings show that SF may play a role in preventing Parkinson's disease.
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PMID:Sulforaphane as an inducer of glutathione prevents oxidative stress-induced cell death in a dopaminergic-like neuroblastoma cell line. 1978 Aug 97

Mutations in PARK7/DJ-1 are associated with autosomal recessive, early onset Parkinson disease (PD). DJ-1 is an atypical peroxiredoxin-like peroxidase that may act as a redox-dependent chaperone and a regulator of transcription. Here we show that DJ-1 plays an essential role in the expression of rearranged during transfection (RET), a receptor for the glial cell line-derived neurotrophic factor, a neuroprotective molecule for dopaminergic neurons, the main target of degeneration in PD. The inducible loss of DJ-1 triggers the establishment of hypoxia and the production of reactive oxygen species that stabilize the hypoxia-inducible factor-1alpha (HIF-1a). HIF-1a expression is required for RET down-regulation. This study establishes for the first time a molecular link between the lack of functional DJ-1 and the glial cell line-derived neurotrophic factor signaling pathway that may explain the adult-onset loss of dopaminergic neurons. Furthermore, it suggests that hypoxia may play an important role in PD.
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PMID:Parkinson disease-associated DJ-1 is required for the expression of the glial cell line-derived neurotrophic factor receptor RET in human neuroblastoma cells. 2039 1

Except for its redox properties, cytochrome c is an inert protein. However, dissociation of the bond between methionine-80 and the heme iron converts the cytochrome into a peroxidase. Dissociation is accomplished by subjecting the cytochrome to various conditions, including proteolysis and hydrogen peroxide (H(2)O(2))-mediated oxidation. In affected cells of various neurological diseases, including Parkinson's disease, cytochrome c is released from the mitochondrial membrane and enters the cytosol. In the cytosol cytochrome c is exposed to cellular proteases and to H(2)O(2) produced by dysfunctional mitochondria and activated microglial cells. These could promote the formation of the peroxidase form of cytochrome c. In this study we investigated the catalytic and cytolytic properties of the peroxidase form of cytochrome c. These properties are qualitatively similar to those of other heme-containing peroxidases. Dopamine as well as sulfhydryl group-containing metabolites, including reduced glutathione and coenzyme A, are readily oxidized in the presence of H(2)O(2). This peroxidase also has cytolytic properties similar to myeloperoxidase, lactoperoxidase, and horseradish peroxidase. Cytolysis is inhibited by various reducing agents, including dopamine. Our data show that the peroxidase form of cytochrome c has catalytic and cytolytic properties that could account for at least some of the damage that leads to neuronal death in the parkinsonian brain.
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PMID:Physical and catalytic properties of a peroxidase derived from cytochrome c. 2162 Sep 67

Mutations in the leucine rich repeat kinase 2 (LRRK2) gene are responsible for autosomal dominant and sporadic Parkinson disease (PD), possibly exerting their effects via a toxic gain of function. A common p.G2019S mutation (rs34637584:A>G) is responsible for up to 30-40% of PD cases in some ethnic populations. Here, we show that LRRK2 interacts with human peroxiredoxin 3 (PRDX3), a mitochondrial member of the antioxidant family of thioredoxin (Trx) peroxidases. Importantly, mutations in the LRRK2 kinase domain significantly increased phosphorylation of PRDX3 compared to wild-type. The increase in PRDX3 phosphorylation was associated with decreased peroxidase activity and increased death in LRRK2-expressing but not in LRRK2-depleted or vector-transfected neuronal cells. LRRK2 mutants stimulated mitochondrial factors involved in apoptosis and induced production of reactive oxygen species (ROS) and oxidative modification of macromolecules. Furthermore, immunoblot and immunohistochemical analysis of postmortem human PD patients carrying the p.G2019S mutation showed a marked increase in phosphorylated PRDX3 (p-PRDX3) relative to normal brain. We showed that LRRK2 mutations increase the inhibition of an endogenous peroxidase by phosphorylation promoting dysregulation of mitochondrial function and oxidative damage. Our findings provide a mechanistic link between the enhanced kinase activity of PD-linked LRRK2 and neuronal cell death.
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PMID:Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death. 2185 Jun 87

Parkinson's disease (PD) is characterized by selective degeneration and loss of dopaminergic neurons in the substantia nigra (SN) of the ventral mid brain leading to dopamine depletion in the striatum. Oxidative stress and mitochondrial damage have been implicated in the death of SN neurons during the evolution of PD. In our previous study on human PD brains, we observed that compared to SN, striatum was significantly protected against oxidative damage and mitochondrial dysfunction. To understand whether brain aging contributes to the vulnerability of midbrain to neurodegeneration in PD compared to striatum, we assessed the status of oxidant and antioxidant markers, glutathione metabolic enzymes, glial fibrillary acidic protein (GFAP) expression and mitochondrial complex I(CI) activity in SN (n = 23) and caudate nucleus (n = 24) during physiological aging in human brains. We observed a significant increase in protein oxidation (P < 0.001), loss of CI activity (P = 0.04) and increased astrocytic proliferation indicated by GFAP expression (P < 0.001) in SN compared to CD with increasing age. These changes were attributed to significant decrease in antioxidant function represented by superoxide dismutase (SOD) (P = 0.03), glutathione (GSH) peroxidase (GPx) (P = 0.02) and GSH reductase (GR) (P = 0.03) and a decreasing trend in total GSH and catalase with increasing age. However, these parameters were relatively unaltered in CD. We propose that SN undergoes extensive oxidative damage, loss of antioxidant and mitochondrial function and increased GFAP expression during physiological aging which might make it more vulnerable to neurotoxic insults thus contributing to selective degeneration during evolution of PD.
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PMID:Increased oxidative damage and decreased antioxidant function in aging human substantia nigra compared to striatum: implications for Parkinson's disease. 2197 58

Laccase- and peroxidase-free tyrosinase has commercial importance in the production of L-3, 4-dihydroxyphenylalanine (L-DOPA), which is mainly used in the treatment of Parkinson's disease. In the present study, isolation of an actinomycetes microbial strain capable of producing only tyrosinase is reported. Among all soil isolates, three individual colonies revealed black color around the colony in the presence of tyrosine. Further screening for laccase and peroxidase activities using syringaldazine denoted that one of the isolates, designated as RSP-T1, is laccase and peroxidase negative and produces only tyrosinase. The microbe was authenticated as Streptomyces antibioticus based on 16S ribotyping. Effective growth of this isolate was noticed with the use of medium (pH 5.5) containing casein acid hydrolysate (10.0 g/l), K(2)HPO(4) (5.0 g/l), MgSO(4) (0.25 g/l), L-tyrosine (1.0 g/l), and agar (15 g/l). The scanning electron micrograph depicted that the microbe is highly branched and filamentous in nature. The enzyme production was positively regulated in the presence of copper sulfate. The impact of different fermentation parameters on tyrosinase production depicted that the maximized enzyme titer values were observed when this isolate was grown at 6.5 pH and at 30 degrees C temperature under agitated conditions (220 rpm). Among all the studied physiological parameters, agitation played a significant role on tyrosinase production. Upon optimization of the parameters, the yield of tyrosinase was improved more than 100% compared with the initial yield.
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PMID:Laccase- and peroxidase-free tyrosinase production by isolated microbial strain. 2237 Mar 50


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