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)

Chronically administered levodopa to Parkinson's disease (PD) patients ultimately produces alterations in motor response. Similarly, in 6-hydroxydopamine lesioned hemi-parkinsonian rats, chronic twice-daily administration of levodopa progressively shortens the duration of contralateral turning, an index of, the wearing-off fluctuations that occur in parkinsonian patients. The pathogenesis of these response alterations involves, in part, upregulation of corticostriatal glutamatergic synaptic transmission. Changes involving kinase and phosphatase signaling pathways within striatal dopaminoceptive medium-spiny neurons now appear to contribute to increased synaptic efficacy of glutamatergic receptors in these neurons. Glutamate-mediated striatal sensitization subsequently modifies basal ganglia output in ways that favor the appearance of parkinsonian motor complications. At the molecular level, transcriptional activation of striatal CREB and cdk5 may contribute to the persistent expression of these levodopa-induced response alterations. Conceivably, a safer and more effective therapy for PD can be provided by drugs that target signaling proteins within striatal spiny neurons or those that interact extracellularly with non-dopaminergic receptors such as AMPA and NMDA, adenosine, adrenergic, opioid, and serotonergic.
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PMID:Glutamate-mediated striatal dysregulation and the pathogenesis of motor response complications in Parkinson's disease. 1237 27

The discovery of cell cycle regulators has directed cell research into uncharted territory. In dividing cells, cell cycle-associated protein kinases, which are referred to as cyclin-dependent-kinases (Cdks), regulate proliferation, differentiation, senescence and apoptosis. In contrast, all Cdks in post-mitotic neurons, with the notable exception of Cdk5, are silenced. Surprisingly, misregulation of Cdks occurs in neurons in a wide diversity of neurological disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Ectopic expression of these proteins in neurons potently induces cell death with hallmarks of apoptosis. Deregulation of the unique, cell cycle-unrelated Cdk5 by its truncated co-activator, p25 and p29, contributes to neurodegeneration by altering the phosphorylation state of non-membrane-associated proteins and possibly through the induction of cell cycle proteins. On the other hand, cycling Cdks such as Cdk2, Cdk4 and Cdk6, initiate death pathways by derepressing E2F-1/Rb-dependent transcription at the neuronal G1/S checkpoint. Thus, Cdk5 and cycling Cdks may have little in common in the healthy CNS, but they likely conspire in leading neurons to their demise.
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PMID:Cycling at the interface between neurodevelopment and neurodegeneration. 1247 66

There is increasing evidence that proteins normally involved in the cell cycle can regulate neuronal programmed cell death (PCD). However, it remains unknown whether cell cycle markers are expressed in normal, postmitotic, postmigratory neurons undergoing PCD in vivo. We have previously shown that natural cell death occurs postnatally in dopamine neurons of the substantia nigra pars compacta (SNpc). PCD can be induced postnatally in these neurons either by intrastriatal injection of the neurotoxin 6-hydroxydopamine (6-OHDA) or by medial forebrain bundle (MFB) axotomy. At the time of induction of death in these models, these neurons are long postmitotic and postmigratory. We have studied three cell cycle markers in these models: 5-bromo-2'-deoxyuridine (BrdU) incorporation (a marker of S phase), cdc2 protein expression (a marker of G2 phase), and expression of MPM2 (a marker of M phase), an epitope phosphorylated by cdc2. We report here that postmitotic dopaminergic neurons undergoing PCD in the SNpc following 6-OHDA and axotomy lesions incorporate BrdU and overexpress cdc2, but do not express MPM2. This is the first in vivo evidence that postmitotic dopamine neurons of the SNpc undergoing apoptosis express markers for S phase and G2 phase. These results raise the possibility that cell cycle regulatory proteins may play a role in the demise of dopaminergic neurons in Parkinson's disease, in which PCD has been postulated to play a role.
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PMID:Ectopic expression of cell cycle markers in models of induced programmed cell death in dopamine neurons of the rat substantia nigra pars compacta. 1250 64

Recent evidence indicates that cyclin-dependent kinases (CDKs, cdks) may be inappropriately activated in several neurodegenerative conditions. Here, we report that cdk5 expression and activity are elevated after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that damages the nigrostriatal dopaminergic pathway. Supporting the pathogenic significance of the cdk5 alterations are the findings that the general cdk inhibitor, flavopiridol, or expression of dominant-negative cdk5, and to a lesser extent dominant-negative cdk2, attenuates the loss of dopaminergic neurons caused by MPTP. In addition, CDK inhibition strategies attenuate MPTP-induced hypolocomotion and markers of striatal function independent of striatal dopamine. We propose that cdk5 is a key regulator in the degeneration of dopaminergic neurons in Parkinson's disease.
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PMID:Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson's disease. 1459 22

Dopamine (DA) is a classical neurotransmitter modulating various brain functions by acting on its specific receptors. In addition, DA is a reactive molecule that has been implicated in neurodegeneration, especially in Parkinson's disease. Here we show that DA inhibited cell growth of dopamine transporter transfected cells by intracellularly blocking cell cycle progression. To pinpoint the site of this effect, we measured DNA distribution and 5-bromo-2'-deoxyuridine (BrdU) incorporation, as well as the levels of the key cell cycle proteins. DA increased number of cells with a G1 DNA content, decreased BrdU incorporation and simultaneously increased cyclin A but had no effect on cyclin D2, D3, E, nor on cdk4 and p21. These results narrowed down the DA effect to the beginning of S phase, suggesting inhibition of the ribonucleotide reductase, an enzyme essential for DNA synthesis. Indeed, measurement of enzyme activity in situ revealed that DA, within 1h of addition to cells labelled with [3H]cytidine, strongly reduced the cell content of [3H]2'-deoxycytidine 5'-triphophate. The time course of this DA effect preceded the cell cycle progression. This novel molecular mechanism of intracellular DA action independent of plasmamembrane receptors may be involved in processes controlling the development and survival of brain dopaminergic neurons.
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PMID:Dopamine inhibits cell growth and cell cycle by blocking ribonucleotide reductase. 1575 80

DNA damage and activation of the cell cycle have been implicated in numerous neurodegenerative diseases, including Alzheimer disease, Parkinson's disease, and amyotrophic lateral sclerosis. To better understand the role of cell cycle proteins in DNA-damage induced neuronal cell death, we examined various cell cycle proteins during camptothecin-induced death of human neuroblastoma cells. We report a rapid induction of p53 and increased expression of p21, concurrent with reduced levels of many cell cycle proteins that regulate G1 to S phase cell cycle progression. However, we found increased levels of cdk2 and cyclin E, and formation of a cyclin E-cdk2-p21 protein complex. DNA damage failed to induce activation and progression of the cell cycle. Finally, camptothecin-induced neuronal cell death occurred concurrent with phosphorylation of histone H2B. Pretreatment of cells with cdk inhibitor olomoucine impeded cdk2-cyclin E accumulation, but not the induction of p53. Olomucine concurrently delayed histone H2B phosphorylation, caspase-3 activation and cell death. These findings suggest that DNA-damage of differentiated neuroblastoma cells induces a rapid p53-mediated inhibition of cell cycle progression and induction of cdk2-cyclin E, followed by caspase-3 activation, phosphorylation of histone and cell death.
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PMID:DNA damage induces cdk2 protein levels and histone H2B phosphorylation in SH-SY5Y neuroblastoma cells. 1615 45

Apoptosis, whether caspase-dependent or caspase-independent, has been implicated as one of the important mechanisms leading to the death of dopaminergic neurons in the substantia nigra of Parkinson's disease patients. Major advances of our understanding of apoptosis have been achieved in studies of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice and monkeys and 6-hydroxydopamine (6-OHDA) toxicity in rats and monkeys. The use of viral vectors to either express anti-apoptotic proteins or to downregulate pro-apoptotic proteins has the major advantage of addressing selective molecular targets, bypassing the blood-brain-barrier to specifically target the nigrostriatal pathway by their stereotaxic application and by the choice of the appropriate virus and promotor. Used thus far have been virus-mediated overexpression of inhibitor of apoptosis proteins, inhibitors of the c-jun-N-terminal kinase (JNK) pathway, inhibitors of calpains and dominant negative inhibitors of the protease activating factor (APAF)-1 and cdk5. Most studies implicate the endogenous, mitochondrial pathway in the apoptosis of dopaminergic neurons. The results suggest that only an inhibition of this pathway upstream of caspase activation will also result in the protection of nigrostriatal dopaminergic terminals and behavioral benefit, whereas an inhibition of caspases alone may not be sufficient to prevent the degeneration of terminals, although it may promote the survival of neuronal cell bodies for some time.
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PMID:Anti-apoptotic gene therapy in Parkinson's disease. 1701 69

Neurodegenerative diseases as Alzheimer's disease, Parkinson's disease and other neurological disorders remain major problem worldwide since is currently no effective treatment. Thus, studying the mechanisms involved in neuronal apoptotic pathways is imperative if drugs that might stop or delay these disease processes are to be synthesized. In recent years it has become evident that mitochondria are key component of the neuronal apoptotic route. In addition to mitochondria, other intracellular components have been implicated in this process. Thus, DNA damage and re-entry into the cell cycle may constitute a common pathway in apoptosis in neurological diseases. The implication of cell cycle in neurodegenerative disorders is supported by data on the brain of patients who showed an increase in cell cycle protein expression. Indeed, studies performed in neuronal cell preparations indicate that re-entry into the cell cycle and, more specifically, an increase in the expression of E2F-1 transcription role of DNA damage/repair as a potential mechanism in cell cycle re-entry. In this context, ataxia telangiectasia mutated protein could be the enzyme responsible for neuronal apoptosis activation. Furthermore, the potential routes involved in E2F-1 induced apoptosis, p53-dependent and p53-independent, are similarly reviewed. Under this hypothesis, multiple pathways have been suggested, including the route of caspases. Finally, given the increasing experimental data on the neuroprotective and antiapoptotic effects of cyclin dependent kinase CDK inhibitory drugs, including flavopiridol, their application for the treatment of neurological disorders is proposed.
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PMID:Implication of the transcription factor E2F-1 in the modulation of neuronal apoptosis. 1717 8

The biochemical pathways involved in neuronal cell death in Parkinson's disease are not completely characterized. Mitochondrial dysfunction, specifically alteration of the mitochondrial complex I, is the primary target of the parkinsonian neurotoxin 1-methyl-4-phenylpyridinium (MPP+) induced apoptosis in neurons. In the present study, we examine the role of caspase-dependent and -independent routes in MPP+-induced apoptosis in rat cerebellar granule neurons (CGNs). We show a distinct increase in the expression of the cell cycle proteins cyclin D, cyclin E, cdk2, cdk4 and the transcription factor E2F-1 following a MPP+ treatment of CGNs. Flavopiridol (FLAV), a broad inhibitor of cyclin-dependent kinases (CDKs), attenuated the neurotoxic effects of MPP+ and significantly attenuates apoptosis mediated by MPP+ 200 microM. Likewise, the antioxidant vitamin E (vit E) increases neuronal cell viability and attenuates apoptosis induced by MPP+. Moreover, the expression levels of cyclin D and E2F-1 induced by this parkinsonian neurotoxin were also attenuated by vit E. Since, the broad-spectrum caspase inhibitor zVAD-fmk did not attenuate MPP+-induced apoptosis in CGNs, our data provide a caspase-independent mechanism mediated by neuronal reentry in the cell cycle and increased expression of the pro-apoptotic transcription factor E2F-1. Our results also suggest a potential role of oxidative stress in neuronal reentry in the cell cycle mediated by MPP+. Finally, our data further support the therapeutic potential of flavopiridol, for the treatment of Parkinson's disease.
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PMID:Inhibition of cyclin-dependent kinases is neuroprotective in 1-methyl-4-phenylpyridinium-induced apoptosis in neurons. 1734 87

The mechanisms involved in neuronal loss in Parkinson's disease (PD) are not known, although recent studies performed in PD experimental models suggest that cdk5/p25 plays a predominant role. In the present study, we examined the gyrus cinguli of cases with PD and compared them with age-matched controls, and we demonstrated an activation of the calpain/cdk5 pathway. We found an increase in the p25/p35 immunoreactivity ratio and in the expression of transcription factor E2F-1. Our results implicate the cdk5/p25 pathway and re-entry into the cell cycle in the process of neuronal loss in patients with PD.
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PMID:Activation of the calpain/cdk5/p25 pathway in the girus cinguli in Parkinson's disease. 1797 53


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