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)

Dopaminergic and glutamatergic neurotransmissions in the striatum play an essential role in motor- and reward-related behaviors. Dysfunction of these neurotransmitter systems has been found in Parkinson's disease, schizophrenia, and drug addiction. Cyclin-dependent kinase 5 (CDK5) negatively regulates postsynaptic signaling of dopamine in the striatum. This kinase also reduces the behavioral effects of cocaine. Here we demonstrate that, in addition to a postsynaptic role, CDK5 negatively regulates dopamine release in the striatum. Inhibitors of CDK5 increase evoked dopamine release in a way that is additive to that of cocaine. This presynaptic action of CDK5 also regulates glutamatergic transmission. Indeed, inhibition of CDK5 increases the activity and phosphorylation of N-methyl-d-aspartate receptors, and these effects are reduced by a dopamine D1 receptor antagonist. Using mice with a point mutation of the CDK5 site of the postsynaptic protein DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, molecular mass of 32 kDa), in the absence or in the presence of a dopamine D1 receptor antagonist, we provide evidence that CDK5 inhibitors potentiate dopaminergic transmission at both presynaptic and postsynaptic locations. These findings, together with the known ability of CDK5 inhibitors to prevent degeneration of dopaminergic neurons, suggest that this class of compounds could potentially be used as a novel treatment for disorders associated with dopamine deficiency, such as Parkinson's disease.
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PMID:Cyclin-dependent kinase 5 regulates dopaminergic and glutamatergic transmission in the striatum. 1476 20

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa therapy for Parkinson's disease. Although changes affecting D(1) and D(2) dopamine receptors have been studied in association with this condition, no causal relationship has yet been established. Taking advantage of a monkey brain bank constituted to study levodopa-induced dyskinesia, we report changes affecting D(1) and D(2) dopamine receptors within the striatum of normal, parkinsonian, nondyskinetic levodopa-treated parkinsonian, and dyskinetic levodopa-treated parkinsonian animals. Whereas D(1) receptor expression itself is not related to dyskinesia, D(1) sensitivity per D(1) receptor measured by D(1) agonist-induced [(35)S]GTPgammaS binding is linearly related to dyskinesia. Moreover, the striata of dyskinetic animals show higher levels of cyclin-dependent kinase 5 (Cdk5) and of the dopamine- and cAMP-regulated phosphoprotein of 32kDa (DARPP-32). Our data suggest that levodopa-induced dyskinesia results from increased dopamine D(1) receptor-mediated transmission at the level of the direct pathway.
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PMID:Increased D1 dopamine receptor signaling in levodopa-induced dyskinesia. 1551 76

Nigral cell death in Parkinson's disease is characterized by glial cell activation leading to inflammatory changes. Osteopontin (OPN) is a glycosylated phosphoprotein that is induced by inflammatory mediators and which we have previously shown to be present in the substantia nigra. However, the role of OPN in the nigral inflammation is not known. We now report on the effects of lipopolysaccharide (LPS)-induced glial cell activation in the substantia nigra of rats on OPN expression. LPS administration induced dopaminergic cell death as shown by reduced nigral tyrosine hydroxylase immunoreactivity. There was a corresponding time-dependent increase in both OPN mRNA, which was maximal at 48 h, and protein levels, which peaked at 72 h before returning to control levels by 120 h. This increase was accompanied by marked reactive gliosis as shown by increased OX-42, glial fibrillary acidic protein (GFAP) and ED1 immunoreactivity. OX-42-positive cells increased in a time-dependent manner, peaking at 72 h before returning to control levels at 120 h. Similarly, ED1-positive cells were present in their greatest numbers at 24 h but then gradually declined. These changes mirrored the alterations occurring in OPN protein and OPN mRNA, respectively. In contrast, GFAP-positive cells only started to increase in number at 120 h. Colocalization studies showed that OPN was present in both ED1- and OX-42-positive cells but not in GFAP-positive cells. These data confirm that intranigral injection of LPS induces a rapid and marked gliosis that accompanies the loss of tyrosine hydroxylase-positive neurones and suggest that, after glial cell activation, enhanced expression of OPN occurs linked to increased numbers of microglia and/or macrophages. This suggests that OPN may be functionally important in the control of inflammatory changes.
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PMID:Increased osteopontin expression following intranigral lipopolysaccharide injection in the rat. 1586 84

Nigrostriatal dopamine depletion disrupts striatal medium spiny neuron morphology in Parkinson's disease and modulates striatal synaptic plasticity in animal models of parkinsonism. We demonstrate that long-term nigrostriatal dopamine depletion in the rat induces evolving changes in the phosphorylation of striatal proteins critical for synaptic plasticity. Dopamine depletion increased the phosphorylation of the alpha isoform of calcium-calmodulin-dependent protein kinase II (CaMKIIalpha) at Thr286, a site associated with enhanced autonomous kinase activity, but did not alter total levels of CaMKIIalpha or other synaptic proteins. Dopamine depletion decreased CaMKIIalpha levels in postsynaptic density-enriched fractions without significant changes in other proteins. The activity of protein phosphatase 1 (PP1), a postsynaptic phosphatase that dephosphorylates CaMKII, is regulated by DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa). Dopamine depletion had no effect on DARPP-32 phosphorylation at Thr34, but increased DARPP-32 phosphorylation at Thr75. Levodopa administration reversed the increased phosphorylation of both CaMKIIalpha and DARPP-32. Normal ageing increased the levels of PP1(gamma1 isoform) but decreased levels of the PP1gamma1-targeting proteins spinophilin and neurabin. Elevated phosphorylations of CaMKIIalpha and DARPP-32 were maintained for up to 20 months after dopamine depletion. However, phosphorylation of the CaMKII-PP1 substrate, Ser831 in the glutamate receptor GluR1 subunit, was increased only after sustained (9-20 months) dopamine depletion. Interaction of ageing-related changes in PP1 with the dopamine depletion-induced changes in CaMKIIalpha may account for enhanced GluR1 phosphorylation only after long-term dopamine depletion. These evolving changes may impact striatal synaptic plasticity, Parkinson's disease progression and the changing efficacy and side-effects associated with dopamine replacement therapy.
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PMID:Dopamine depletion alters phosphorylation of striatal proteins in a model of Parkinsonism. 1602 14

The neuronal phosphoprotein alpha-synuclein has been increasingly implicated in the pathogenesis of Parkinson's disease (PD) and other neurodegenerative diseases; however, the exact function of alpha-synuclein still remains illusive. Suitable antibodies (Abs) specific for the gene of interest are indispensable for studying biological and immunological properties of the target gene. Here, we report not only the generation and characterization of monoclonal Abs, Syn-1 and Syn-17, against human alpha-synuclein, but also the epitope mapping by using recombinant synuclein family proteins and various GST fusion proteins of human alpha-synuclein domains. Syn-17 recognizes human and rodent alpha-synuclein, and its epitope is localized within residues 97-99 and 101 of alpha-synuclein. In contrast, the Syn-1 epitope is localized in residues 121 and 122 of human alpha-synuclein, and Syn-1 recognizes only human but not rodent alpha-synuclein, indicating that it can be utilized as a useful reagent for studying human alpha-synuclein transgenic mouse and zebrafish lines.
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PMID:Fine epitope mapping of monoclonal antibodies specific to human alpha-synuclein. 1638 Feb 7

Neurodegenerative disorders (ND) encompass clinically and genetically heterogeneous diseases with considerable overlap of their clinical, neuropathological and molecular phenotype. Various causes of neurodegeneration in disease may affect eventually the same proteins within protein networks. To identify common changes in ND, we compared brain protein changes detected by 2-D electrophoresis in four mouse models for ND: (i) Parkinson's disease, (ii) Huntington's disease, (iii) prion disease Scrapie, and (iv) a model for impaired synaptic transmission. To determine specificity of these changes for ND, we extended the scope of our investigation to three neurological conditions that do not result in neurodegeneration (non-ND). We detected 12 to 216 consistent qualitative or quantitative protein changes in individual ND and non-ND models when compared to controls. Up to 36% of these proteins were found to be altered in multiple disease states (at least three) and were therefore termed nodal point proteins. Alterations in alpha B-Crystallin and splicing factor 3b (subunit 4) occurred in at least three ND but not in non-ND. In contrast, alterations in peroxiredoxin 1 and 3, astrocytic phosphoprotein PEA15, complexin 2 and aminoacylase 1 were common to both ND and non-ND. Finally, we investigated the expression pattern of the nodal point proteins in three inbred mouse strains and found different protein abundance (expression polymorphisms) in all cases. Nodal point proteins showing expression polymorphisms may be candidate proteins for disease associated modifiers.
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PMID:Comparative proteomics in neurodegenerative and non-neurodegenerative diseases suggest nodal point proteins in regulatory networking. 1688 17

Parkinson's disease (PD) is characterised by the loss of dopaminergic neurones in the substantia nigra (SN) but the pathogenic mechanism remains unknown. Cell death involves oxidative stress and inflammatory mechanisms, and these may be altered by the actions of the glycosylated phosphoprotein osteopontin (OPN). OPN is present in the rat SN, but its presence in human and non-human primate brain has not been extensively studied. Both OPN mRNA and protein were present in the normal marmoset SN, and OPN protein was localised to nigral neurones although these were not dopaminergic cells and it was not present in glial cells. In contrast, OPN protein was found in dopaminergic neurones in the normal human SN but again not in glial cells with some accumulation in the extracellular matrix. Following MPTP treatment of common marmosets, OPN protein expression was decreased, although its mRNA levels were unchanged and it was not present in either activated microglia or astrocytes. In the SN in PD, OPN protein expression was decreased in the remaining dopaminergic neurones and it was present in activated microglia but not in astrocytes. This was not specific to PD as OPN protein expression was also decreased in the SN in multiple system atrophy and progressive supranuclear palsy with an identical localisation of the protein. The presence of OPN in the normal human and non-human primate SN coupled to its decreased expression following nigral cell degeneration suggests that it may play an important role in dopaminergic neurone survival.
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PMID:Osteopontin expression in substantia nigra in MPTP-treated primates and in Parkinson's disease. 1696 83

The correct identity and functional capacity of transplanted dopamine (DA) neurons derived in vitro from embryonic stem (ES) cells is a critical factor for the development of an ES cell-based replacement therapy for Parkinson's disease. We transplanted primate Cyno-1 ES cells differentiated in vitro for 4 (progenitor ES cells) or 6 (differentiated ES cells) weeks, or control fetal primate cells into the striatum of hemi-parkinsonian rats. Partial behavioral recovery in amphetamine-induced rotation was correlated with the number of ES-derived tyrosine hydroxylase-positive (TH+) neurons in the grafts (r=0.5, P<0.05). Post mortem analysis of ES-derived grafts revealed TH+neurons with mature morphology, similar to fetal DA neurons, and expression of midbrain transcription factors, such as Engrailed (En) and Nurr-1. While the total number of TH+neurons was not different between the two groups, TH/En co-expression was significantly higher (>90%) in grafts from differentiated ES cells than in grafts derived from progenitor cells (<50%), reflecting a more heterogeneous cellular composition. Within the grafts there was an overlap between ES-derived TH+axonal arbors and clusters of primate ES-derived striatal neurons expressing brain factor 1 (Bf-1, Foxg1) and DA and cAMP-regulated phosphoprotein (DARPP-32). Such overlap was never observed for other regional transcription factors that define neighboring forebrain domains in the developing brain, such as Nkx2.1 (medial ganglionic eminence), Nkx2.2 (pallidal and diencephalic progenitors) or Pax6 (dorsal telencephalic progenitors). Despite the heterogeneity of ES-derived graft cell composition, these results demonstrate normal phenotypic specification, conserved natural axonal target selectivity and functionality of DA neurons derived from primate ES cells.
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PMID:Transplanted dopamine neurons derived from primate ES cells preferentially innervate DARPP-32 striatal progenitors within the graft. 1706 92

Neural stem cells (NSCs) possess high potencies of self-renewal and neuronal differentiation. We explored here whether transplantation of human NSCs cloned by v-myc gene transfer, HB1.F3 cells, is a feasible therapeutic option for Parkinson's disease. In vivo, green fluorescent protein-labeled HB1.F3 cells (200,000 viable cells in 3 microl of PBS) when stereotaxically transplanted (same-day lesion-transplant paradigm) into the 6-hydroxydopamine-lesioned striatum of rats significantly ameliorated parkinsonian behavioral symptoms compared with controls (vehicle, single bolus, or continuous minipump infusion of trophic factor, or killed cell grafts). Such graft-derived functional effects were accompanied by preservation of tyrosine hydroxylase (TH) immunoreactivity along the nigrostriatal pathway. Grafted HB1.F3 cells survived in the lesioned brain with some labeled with neuronal marker mitogen-activated protein 2 and decorated with synaptophysin-positive terminals. Furthermore, endogenous neurogenesis was activated in the subventricular zone of transplanted rats. To further explore the neuroprotective mechanisms underlying HB1.F3 cell transplantation, we performed cell culture studies and found that a modest number of HB1.F3 cells were TH and dopamine and cAMP-regulated phosphoprotein 32 positive, although most cells were nestin positive, suggesting a mixed population of mature and immature cells. Administration of the HB1.F3 supernatant to human derived dopaminergic SH-SY5Y cells and fetal rat ventral mesencephalic dopaminergic neurons protected against 6-hydroxydopamine neurotoxicity by suppressing apoptosis through Bcl-2 upregulation, which was blocked by anti-stem cell factor antibody alone, the phosphatidylinositol 3-kinase/Akt inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one] alone, or a combination of both. These results suggest that HB1.F3 cell transplantation exerts neuroprotective effects against dopaminergic depletion in vitro and in vivo because of trophic factor secretion and neuronal differentiation.
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PMID:Transplantation of human neural stem cells exerts neuroprotection in a rat model of Parkinson's disease. 1713 12

Intrastriatal transplantation of fetal ventral mesencephalon (VM) tissue provides the potential to alleviate motor symptoms of Parkinson's disease (PD) and levodopa-induced dyskinesia (LID). However, the degree of recovery varies among individuals with an incidence of "off-phase", graft-induced dyskinesia (GID) in some patients. We hypothesised that this variability is due to the heterogeneous nature of dopaminergic neurons in the transplant. We therefore investigated this in the unilateral 6-hydroxydopamine-lesioned rat model of PD. These animals were primed to develop LID and then transplanted with fetal VM into the caudal aspects of the striatum. No GID was observed but in a significant number of animals the transplants ameliorated LID. There was a correlation between the degree of behavioural and LID recovery with the number of A9 dopaminergic neurons in the transplant, based on their expression of a G-protein-coupled inward rectifying current potassium channel (Girk2). Furthermore, we showed that LID development is related to an abnormal expression profile of cyclin-dependent kinase 5 (Cdk5) and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) in the striatum and that intrastriatal VM transplants normalised both Cdk5 expression and DARPP-32 phosphorylation in animals exhibiting functional improvement. These results suggest that an A9 dopaminergic neuron-enriched transplant may be the key to an effective PD cell replacement therapy through normalisation of the altered striatal expression of Cdk5/DARPP-32.
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PMID:The importance of A9 dopaminergic neurons in mediating the functional benefits of fetal ventral mesencephalon transplants and levodopa-induced dyskinesias. 1718 99


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