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 effects of HSV-1 amplicon and polyethyleneimine (PEI)-mediated transfection of dominant negative FGF receptor-1 mutant FGFR1(TK-) into the rat brain substantia nigra (SN) were examined in vivo to model the reduced FGF signaling documented to occur in Parkinson's disease. The number of SN neurons that expressed tyrosine hydroxylase (TH) was significantly reduced following HSV-1 FGFR1(TK-) intranigral delivery and similar changes were observed after PEI-mediated FGFR1(TK-) transfections. Further, we also observed a significantly lower striatal dopamine content following the PEI transfection of FGFR1(TK-). Thus, we conclude that reduced FGF signaling in the SN of Parkinsonian patients could play a role in the impaired dopaminergic transmission associated with the degenerative disease.
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PMID:Transfection of tyrosine kinase deleted FGF receptor-1 into rat brain substantia nigra reduces the number of tyrosine hydroxylase expressing neurons and decreases concentration levels of striatal dopamine. 1603 6

At this large and varied meeting on neuropharmacotherapy, progress was reported on the newer more selective antipsychotics. The selective D(2) dopamine receptor partial agonist, aripiprazole (Otsuka Pharmaceutical Co Ltd) was recently proved effective over the medium term. The atypical antipsychotics generally, such as clozapine, have a good side effect profile and better patient compliance, even in Parkinson's disease (PD). Reboxetine (Pharmacia & Upjohn AB), having a far greater selectivity for norepinephrine reuptake inhibition than for serotonin or dopamine reuptake, is of particular value in treating depression. Paroxetine (Novo Nordisk A/S), a selective serotonin reuptake inhibitor (SSRI), has just completed a multicenter clinical trial, being effective in about 50% of cases of post-traumatic stress disorder. A meta-analysis of trials of other uptake inhibitors showed that ability to block serotonin (rather than norepinephrine) uptake correlated well with efficacy. Bipolar and other disorders were hoped to benefit from more selective agents in the future, the potential for which has been revealed through basic neurobiology, with, for example, only non-alpha7 nicotinic receptor subunits being expressed by those interneurons mediating nicotinic responses. An open label, 30-day study of a pyrrolopyrimidine, the corticotrophin releasing factor (CRF) type 1 receptor inhibitor, NBI-30775 (Neurocrine Biosciences Inc/Janssen Pharmaceutica NV) produced good antidepressant effects, but has had to be abandoned as a product due to indications of potential liver damage. Similarly, although glial-derived neurotrophic factor (GDNF) had proved ineffective in a 1999 trial for PD, due to failure to access the striatum, there was however much evidence to suggest that small molecule agonists of the TRK-B receptor should be effective. Of these, quinones such as L-783281 (Merck Research Laboratories) appear to activate all TRK subtypes by a common intracellular, rather than receptormediated action, which may limit their usefulness. Although such agents would have many potential applications, it is likely that highly selective receptor activation will be needed.
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PMID:CINP 2000 - Collegium Internationale Neuro-Psychopharmacologicum 22nd Congress. 1604 59

Calpains are proteases that catalyze the limited cleavage of target proteins in response to Ca(2+) signaling. Because of their involvement in pathological conditions such as post-ischemic injury and Alzheimer and Parkinson disease, calpains form a class of pharmacologically significant targets for inhibition. We have determined the sequence preference for the hydrolysis of peptide substrates of the ubiquitous mu-calpain isoform by a peptide library-based approach using the proteolytic core of mu-calpain (muI-II). The approach, first described by Turk et al. (Turk, B. E., Huang, L. L., Piro, E. T., and Cantley, L. C. (2001) Nat. Biotechnol. 19, 661-667), involved the digestion of an N-terminally acetylated degenerate peptide library in conjunction with Edman sequencing to determine the specificity for residues found at primed positions. The cleavage consensus for these positions was then used to design a second, partially degenerate library, to determine specificity at unprimed positions. We have improved upon the original methodology by using a degenerate peptide dendrimer for determination of specificity at unprimed positions. By using this modified approach, the complete cleavage specificity profile for muI-II was determined for all positions flanking the cleaved peptide. A previously known preference of calpains for hydrophobic amino acids at unprimed positions was confirmed. In addition, a novel residue specificity for primed positions was revealed to highlight the importance of these sites for substrate recognition. The optimal primed site motif (MER) was shown to be capable of directing cleavage to a specific peptide bond. Accordingly, we designed a fluorescent resonance energy transfer-based substrate with optimal cleavage motifs on the primed and non-primed sides (PLFAER). The mu-calpain core shows a far greater turnover rate for our substrate than for those based on the cleavage site of alpha-spectrin or the proteolytic sequence consensus compiled from substrate alignments.
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PMID:Determination of peptide substrate specificity for mu-calpain by a peptide library-based approach: the importance of primed side interactions. 1621 85

It is well documented that manganese neurotoxicity induces clinical symptoms similar to those of idiopathic Parkinson's disease. Although microglial cytotoxic mediator-induced neurotoxicity is suggested, the mechanism by which manganese up-regulates cytotoxic mediator, such as nitric oxide (NO), remains poorly understood. Therefore, in this study, we investigated the mechanism of manganese on induction of iNOS in microglial cells. iNOS promoter/luciferase assay revealed that manganese (500 (M) regulated the iNOS expression at the transcriptional level. Immunoblot analysis also revealed that phosphorylation levels of ERK, JNK MAPKs and Akt (PKB, PI 3-kinase downstream effector), were increased. Both protein and mRNA levels of iNOS expression were abrogated by specific inhibitors, SP600125 (JNK inhibitor, 20 microM), PD98059 (ERKs inhibitor, 50 microM), or LY294002 (PI 3-kinase inhibitor, 20 microM), but not by SB203580 (20 microM), a p38 specific inhibitor. These data lead to the conclusion that manganese regulates the iNOS expression at the transcriptional level in BV2 microglial cells and the increased iNOS protein expression is mediated via both JNK-ERK MAPK and PI3K/Akt signaling pathways, but not via p38 MAPK pathway. Increased iNOS protein level was also found in RAW264.7 murine macrophage cells.
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PMID:Manganese induces inducible nitric oxide synthase (iNOS) expression via activation of both MAP kinase and PI3K/Akt pathways in BV2 microglial cells. 1641 67

In the human embryo, from approximately 6 weeks gestational age (GA), dopaminergic (DA) neurons can be found in the ventral mesencephalon (VM). More specifically, the post-mitotic neurons are located in the ventral part of the tegmentum (VT), whereas no mature DA neurons are found in the neighboring dorsal part. We used Affymetrix HG-U133 GeneChip technology to compare genome-wide expression profiles of ventral and dorsal tegmentum from 8 weeks GA human embryos, in order to identify genes involved in specification, differentiation, and survival of mesencephalic DA (mDA) neurons. Known mDA marker genes including ALDH1A1, DAT1, VMAT2, TH, CALB1, NURR1, FOXA1, GIRK2, PITX3, RET, and DRD2 topped the list of 96 genes from HG-U133A with higher expression in VT, validating the experimental set-up. In addition, 28 probes from HG-U133B were identified whereof most are annotated to UniGene clusters with no gene associated or to genes of unknown function. Of these, the fifteen most regulated transcripts, representing changes down to 56% could be verified by quantitative real-time PCR (Q-PCR) on a developmental series of subdissected human embryonic and fetal brain material, resulting in not only a regional but also a temporal expression profile. This revealed a distinct DA-associated profile for in particular a putative transcription factor (FLJ45455) and the uncharacterized transmembrane proteins KIAA1145 and SLC10A4. The data presented here may help to device cell replacement and regenerative therapies for Parkinson's disease (PD).
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PMID:Identification of novel genes regulated in the developing human ventral mesencephalon. 1647 50

Increasing evidence has suggested an important role for rotenone in the pathogenesis of Parkinson's disease (PD). In this report, sequential linking of two culture systems, monocytic THP-1 cell line and SH-SY5Y neuroblastoma, was utilized. The supernatant from rotenone-stimulated THP-1 cells was used as the incubating medium for the second culture which adopted cells of the SH-SY5Y neuroblastoma. At 6.25-50 nM, concentrations that were nontoxic to SH-SY5Y directly, rotenone induced dose-dependent cell death on SH-SY5Y through stimulating monocyte THP-1 within a period of 48 h. Cytotoxicity was determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Hoechst 33258 staining revealed that the treatment of SH-SY5Y with rotenone-stimulated THP-1 supernatant resulted in condensed nuclei and a decrease in cell size. Apoptotic rate measured by flow cytometric analysis indicated that at 25 and 50 nM, the percentage of apoptotic SH-SY5Y cells accumulated to 31.5% and 37.0% respectively. We further investigated whether rotenone (50 nM) activated mitogen-activated protein kinase (MAPK) cascades, and found it had effect on p38 MAPK and ERK in THP-1 cells, but not JNK. Pretreatment of THP-1 cells with the MAPK kinase inhibitor, PD98059, inhibited THP-1 cell-mediated rotenone neurotoxicity towards SH-SY5Y, whereas the p38 MEK inhibitor, SB203580, had no effect. These results suggested that activation of microglia intracellular signaling pathway may also involve in microglia-enhanced rotenone neurotoxicity.
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PMID:Monocyte-mediated rotenone neurotoxicity towards human neuroblastoma SH-SY5Y: role of mitogen-activated protein kinases. 1681 71

Mutations in the parkin gene are responsible for a common familial form of Parkinson's disease. As parkin encodes an E3 ubiquitin ligase, defects in proteasome-mediated protein degradation are believed to have a central role in the pathogenesis of Parkinson's disease. Here, we report a novel role for parkin in a proteasome-independent ubiquitination pathway. We have identified a regulated interaction between parkin and Eps15, an adaptor protein that is involved in epidermal growth factor (EGF) receptor (EGFR) endocytosis and trafficking. Treatment of cells with EGF stimulates parkin binding to both Eps15 and the EGFR and promotes parkin-mediated ubiquitination of Eps15. Binding of the parkin ubiquitin-like (Ubl) domain to the Eps15 ubiquitin-interacting motifs (UIMs) is required for parkin-mediated Eps15 ubiquitination. Furthermore, EGFR endocytosis and degradation are accelerated in parkin-deficient cells, and EGFR signalling via the phosphoinositide 3-kinase (PI(3)K)-Akt pathway is reduced in parkin knockout mouse brain. We propose that by ubiquitinating Eps15, parkin interferes with the ability of the Eps15 UIMs to bind ubiquitinated EGFR, thereby delaying EGFR internalization and degradation, and promoting PI(3)K-Akt signalling. Considering the role of Akt in neuronal survival, our results have broad new implications for understanding the pathogenesis of Parkinson's disease.
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PMID:A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K-Akt signalling. 1688 Aug 10

Two atypical inhibitors of the dopamine transporter, benztropine, used in the treatment of Parkinson's disease, and bupropion, used as an antidepressant, show very different psychostimulant effects when compared with another inhibitor, cocaine. Taking advantage of the differential sensitivity of the dopamine and the norepinephrine transporters (DAT and NET) to benztropine and bupropion, we have used site-directed mutagenesis to produce gain-of-function mutants in NET which demonstrate that Ala279 in the trans-membrane domain 5 (TM5) and Ser359 in the TM7 of DAT are responsible for the higher sensitivity of DAT to both bupropion and benztropine. Substitution of these two DAT residues into the NET background does not alter the potency of NET-selective inhibitors, such as desipramine. The results from experiments examining the ability of DAT-selective inhibitors to displace [3H]nisoxetine binding in NET gain-of-function mutants suggest that Ser359 contributes to the initial binding of the inhibitor, and that Ala279 may influence subsequent steps involved in the blockade of translocation. Thus, these studies begin to identify residues that are important for the unique molecular interactions of benztropine and bupropion with the DAT, and that ultimately may contribute to the distinct behavioral actions of these drugs.
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PMID:Gain of function mutants reveal sites important for the interaction of the atypical inhibitors benztropine and bupropion with monoamine transporters. 1692 64

The specific expression of fibroblast growth factor 20 (FGF-20) in the adult substantia nigra and the association between FGF-20 mutations and Parkinson's disease provoked exploration of the function of this growth factor. We show by gain- and loss-of-function in vitro experiments that FGF-20 promotes survival and stimulates dopamine (DA) release in a calbindin-negative subset of cells that are preferentially lost in Parkinson's disease. FGF-20 selectively activates tyrosine hydroxylase in calbindin-negative neurons. In the adult substantia nigra, calbindin-negative neurons specifically express high levels of FGFR1 (FGF receptor 1). These data show that FGF signals to elevate DA levels and protect the specific midbrain neuron type at most risk in Parkinson's patients.
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PMID:A specific survival response in dopamine neurons at most risk in Parkinson's disease. 1698 46

Glial cell line-derived neurotrophic factor (GDNF) has shown robust neuroprotective and neuroreparative activities in various animal models of Parkinson's Disease or amyotrophic lateral sclerosis (ALS). The successful use of GDNF as a therapeutic in humans, however, appears to have been hindered by its poor bioavailability to target neurons in the central nervous system (CNS). To improve delivery of exogenous GDNF protein to CNS motor neurons, we employed chemical conjugation techniques to link recombinant human GDNF to the neuronal binding fragment of tetanus toxin (tetanus toxin fragment C, or TTC). The predominant species present in the purified conjugate sample, GDNF:TTC, had a molecular weight of approximately 80 kDa as determined by non-reducing SDS-PAGE. Like GDNF, addition of GDNF:TTC to culture media of neuroblastoma cells expressing GFRalpha-1/c-RET produced a dose-dependent increase in cellular phospho-c-RET levels. Treatment of cultured midbrain dopaminergic neurons with either GDNF or the conjugate similarly promoted both DA neuron survival and neurite outgrowth. However, in contrast to mice treated with GDNF by intramuscular injection, mice receiving GDNF:TTC revealed intense GDNF immunostaining associated with spinal cord motor neurons in fixed tissue sections. That GDNF:TTC provided neuroprotection of axotomized motor neurons in neonatal rats further revealed that the conjugate retained its GDNF activity in vivo. These results indicate that TTC can serve as a non-viral vehicle to substantially improve the delivery of functionally active growth factors to motor neurons in the mammalian CNS.
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PMID:A glial cell line-derived neurotrophic factor (GDNF):tetanus toxin fragment C protein conjugate improves delivery of GDNF to spinal cord motor neurons in mice. 1702 Jul 49


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