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 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

alpha-Synuclein is a presynaptic protein that accumulates abnormally in Lewy bodies of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Its physiological function and role in neuronal death remain poorly understood. Recent immunohistochemical studies suggest that cell cycle-related phenomena may play a role in the pathogenesis of Alzheimer's disease and perhaps other neurodegenerative disorders. In this investigation, we examined the effects of alpha-synuclein expression levels on cell cycle indices in PC12 cells engineered to conditionally induce alpha-synuclein expression upon withdrawal of doxycycline. Over-expression of alpha-synuclein resulted in enhanced proliferation rate and enrichment of cells in the S phase of the cell cycle. This was associated with increased accumulation of the mitotic factor cyclin B and down-regulation of the tumor suppressor retinoblastoma 2. Additionally, ERK1/2, key molecules in proliferation signaling, were highly phosphorylated. Immunohistochemical studies on postmortem brains revealed intense cyclin B immunoreactivity in Lewy bodies in cases with DLB and to a lesser extent in PD. We propose that elevated expression of alpha-synuclein causes changes in cell cycle regulators through ERK activation leading to apoptosis of postmitotic neurons. These changes in cell cycle proteins are also associated with ectopic expression of cyclin B in Lewy bodies.
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PMID:Cell cycle aberrations by alpha-synuclein over-expression and cyclin B immunoreactivity in Lewy bodies. 1288 76

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

In dividing cells, cyclin-dependent kinases (Cdks) are cell cycle-associated protein kinases that regulate proliferation, differentiation, senescence, and apoptosis. In neurons that no longer divide, deregulation of Cdks, especially Cdk5, occurs in many neurological disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Cdk5 is a unique member of the Cdk family because it does not play a critical role in cell cycle progression, and it is not activated by a cyclin. Instead, Cdk5 normally is activated by the regulatory protein p35. This Cdk5/p35 activity has emerged as an important regulator of proper development of the mammalian central nervous system. In vitro studies suggest that aberrant activation of Cdk5 by an endogenous truncated version (p25) of p35 might be a key event in the process of neurodegeneration. One enzyme responsible for cleavage of p35 to form p25 is calpain, a calcium-activated protease that has been shown to be involved in neuronal cell death. Recent studies provided important in vivo evidence that hyperactivation and redistribution of Cdk5 by p25 plays an essential role in the phosphorylation of "pathological" substrates (such as tau) and the cell death of neurons in experimental models of AD and PD. Because amyloid beta peptide, the primary neurotoxic component of amyloid plaques in AD, has been shown to increase the conversion of p35 to p25, aberrant activation of Cdk5 by p25 might be a pathway connecting amyloid beta toxicity to tau hyperphosphorylation in AD.
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PMID:Cyclin-dependent kinase 5--a neuronal killer? 1468 76

Rotenone is an inhibitor of mitochondrial complex I that produces a model of Parkinson's disease (PD), where neurons undergo apoptosis by caspase-dependent and/or caspase-independent pathways. Inhibition of calpains has recently been shown to attenuate neuronal apoptosis. This study aims to establish for the first time, the time-point of calpain activation with respect to the caspase activation and the possibility of cell cycle re-entry in rotenone-mediated cell death. Immunoblot results revealed calpain activation occurred at 5, 10h prior to caspase-3 activation (at 15 h), suggesting calpain activation was an earlier cellular event compared to caspase activation in the rotenone-mediated apoptosis. In addition, an upregulation of phospho-p53 was observed at 21 h. However, no expression or upregulation of cell cycle regulatory proteins including cdc25a, cyclin-D1 and cyclin-D3 were observed, strongly suggesting that cell cycle re-entry did not occur. These findings provide new insights into the differential patterns of calpain and caspase activation that result from rotenone poisoning and which may be relevant to the therapeutic management of PD.
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PMID:Early induction of calpains in rotenone-mediated neuronal apoptosis. 1641 76

Loss-of-function mutations of the parkin gene causes an autosomal recessive juvenile-onset form of Parkinson's disease (AR-JP). Parkin was shown to function as a RING-type E3 ubiquitin protein ligase. However, the function of parkin in neuronal cells remains elusive. Here, we show that expression of parkin-potentiated adenosine triphosphate (ATP)-induced currents that result from activation of the P2X receptors which are widely distributed in the brain and involved in neurotransmission. ATP-induced inward currents were measured in mock-, wild-type or mutant (T415N)-parkin-transfected PC12 cells under the conventional whole-cell patch clamp configuration. The amplitude of ATP-induced currents was significantly greater in wild-type parkin-transfected cells. However, the immunocytochemical study showed no apparent increase in the number of P2X receptors or in ubiquitin levels. The increased currents were attenuated by inhibition of cAMP-dependent protein kinase (PKA) but not protein kinase C (PKC) or Ca2+ and calmodulin-dependent protein kinase (CaMKII). ATP-induced currents were also regulated by phosphatases and cyclin-dependent protein kinase 5 (CDK5) via dopamine and cyclic AMP-regulated phosphoprotein (DARPP-32), though the phosphorylation at Thr-34 and Thr-75 were unchanged or rather attenuated. We also tried to investigate the effect of alpha-synuclein, a substrate of parkin and also forming Lysine 63-linked multiubiquitin chains. Expression of alpha-synuclein did not affect the amplitude of ATP-induced currents. Our finding provides the evidence for a relationship between parkin and a neurotransmitter receptor, suggesting that parkin may play an important role in synaptic activity.
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PMID:Parkin potentiates ATP-induced currents due to activation of P2X receptors in PC12 cells. 1682 4

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

Dopamine (DA) neurons derived from stem cells are a valuable source for cell replacement therapy in Parkinson disease, to study the molecular mechanisms of DA neuron development, and for screening pharmaceutical compounds that target DA disorders. Compared with other stem cells, MSCs derived from the adult human bone marrow (BM) have significant advantages and greater potential for immediate clinical application. We report the identification of in vitro conditions for inducing adult human MSCs into DA cells. Using a cocktail that includes sonic hedgehog and fibroblast growth factors, human BM-derived MSCs were induced in vitro to become DA cells in 12 days. Based on tyrosine hydroxylase (TH) expression, the efficiency of induction was determined to be approximately 67%. The cells develop a neuronal morphology expressing the neuronal markers NeuN and beta III tubulin, but not glial markers, glial fibrillary acidic protein and Olig2. As the cells acquire a postmitotic neuronal fate, they downregulate cell cycle activator proteins cyclin B, cyclin-dependent kinase 2, and proliferating cell nuclear antigen. Molecular characterization revealed the expression of DA-specific genes such as TH, Pitx3, Nurr1, DA transporter, and vesicular monoamine transporter 2. The induced MSCs also synthesize and secrete DA in a depolarization-independent manner. The latter observation is consistent with the low expression of voltage gated Na(+) and Ca(2+) channels in the induced MSCs and suggests that the cells are at an immature stage of development likely representing DA neuronal progenitors. Taken together, the results demonstrate the ability of adult human BM-derived MSCs to form DA cells in vitro.
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PMID:Specification of a dopaminergic phenotype from adult human mesenchymal stem cells. 1765 44

The proline-directed serine threonine kinase, Cdk5, is an unusual molecule that belongs to the well-known large family of proteins, cyclin-dependent kinases (Cdks). While it has significant homology with the mammalian Cdk2 and yeast cdc2, unlike the other Cdks, it has little role to play in cell cycle regulation and is activated by non-cyclin proteins, p35 and p39. It phosphorylates a spectrum of proteins, most of them associated with cell morphology and motility. A majority of known substrates of Cdk5 are cytoskeletal elements, signalling molecules or regulatory proteins. It also appears to be an important player in cell-cell communication. Highly conserved, Cdk5 is most abundant in the nervous system and is of special interest to neuroscientists as it appears to be indispensable for normal neural development and function. In normal cells, transcription and activity of Cdk5 is tightly regulated. Present essentially in post-mitotic neurons, its normal activity is obligatory for migration and differentiation of neurons in developing brain. Deregulation of Cdk5 has been implicated in Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease and acute neuronal injury. Regulators of Cdk5 activity are considered as potential therapeutic molecules for degenerative diseases. This review focuses on the role of Cdk5 in neural cells as regulator of cytoskeletal elements, axonal guidance, membrane transport, synaptogenesis and cell survival in normal and pathological conditions.
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PMID:An unusual member of the Cdk family: Cdk5. 1818 83

Oxidative stress has been shown to mediate neuron damage in Parkinson's disease (PD). In the present report, we intend to clarify the intracellular pathways mediating dopaminergic neuron death after oxidative stress production using post-mitotic PC12 cells treated with the neurotoxin 6-hydroxydopamine (6-OHDA). The use of post-mitotic cells is crucial, because one of the suggested intracellular pathways implicated in neuron death relates to the re-entry of neurons (post-mitotic cells) in the cell cycle. We find that 6-OHDA sequentially increases intracellular oxidants, functional cell damage and caspase-3 activation, leading to cell death after 12 h of incubation. Prevention of cell damage by different antioxidants supports the implication of oxidative stress in the observed neurotoxicity. Oxidative stress-dependent phosphorylation of the MAPK JNK and oxidative stress-independent PKB/Akt dephosphorylation are involved in 6-OHDA neurotoxicity. Decrease in p21(WAF1/CIP1) and cyclin-D1 expression, disappearance of the non-phosphorylated band of retinoblastoma protein (pRb), and expression of proliferating cell nuclear antigen, not present in PC12 post-mitotic cells, suggest a re-entry of differentiated cells into cell cycle. Our results indicate that such a re-entry is mediated by oxidative stress and is involved in 6-OHDA-induced cell death. We conclude that at least three intracellular pathways are involved in 6-OHDA-induced cell death in differentiated PC12 cells: JNK activation, cell cycle progression (both oxidative stress-dependent), and Akt dephosphorylation (not related to the increase of oxidants); the three pathways are necessary for the cells to die, since blocking one of them is sufficient to keep the cells alive.
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PMID:Intracellular signaling pathways involved in post-mitotic dopaminergic PC12 cell death induced by 6-hydroxydopamine. 1866 12


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