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)

Persephin (PSP) is a neurotrophic factor of the GDNF family that has been found to promote the survival of multiple populations of neurons. In the present study we have examined: (1) the mechanism of action and the function of PSP on nigrostriatal dopamine neurons and (2) the therapeutic potential of PSP, delivered by neural stem cells (NSCs) in a model of Parkinson's disease. Interestingly we found that the prenatal ventral mesencephalon and the newborn striatum express high levels of PSP mRNA. Moreover, midbrain dopamine neurons express its preferred receptor GFRalpha4, allowing a cis type of action of PSP on dopamine neurons. Primary culture studies showed that PSP is as potent and efficacious as GDNF at promoting both survival and neuritogenesis of midbrain dopamine neurons. To study the function and therapeutic potential of PSP in vivo we engineered NSCs to overexpress PSP. PSP-c17.2 cells were found to stably express PSP mRNA and protein for at least 3 months in vivo, to disperse within the striatum, and to give rise to neurons, astrocytes, and a large proportion of oligodendrocytes that integrated within white matter tracts in the striatum. Moreover, PSP-c17.2 cells enhanced dopamine-dependent behavioral parameters in unlesioned mice and prevented the loss of dopamine neurons and the behavioral impairment of mice receiving intrastriatal 6-OHDA injections. Thus, our findings are consistent with a direct action of PSP on developing and adult midbrain dopamine neurons and suggest that the delivery of PSP by NSCs may constitute a very useful strategy in the treatment of Parkinson's disease.
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PMID:Persephin-overexpressing neural stem cells regulate the function of nigral dopaminergic neurons and prevent their degeneration in a model of Parkinson's disease. 1240 43

Sustained neurotrophic factor treatment in neurodegenerative disorders such as Parkinson's disease is likely to affect both degenerating and intact neurons. To investigate the effect of long-term glial cell line-derived neurotrophic factor (GDNF) overexpression on intact nigrostriatal dopamine neurons, we injected a recombinant lentiviral vector encoding GDNF, or green fluorescent protein, in the right striatum of young adult rats. Thirteen months after viral injection GDNF levels were 4.5 ng/mg tissue in the striatum and 0.9 ng/mg in the substantia nigra as measured by ELISA, representing a 25-100-fold increase above control vector- or nontransduced tissue. GDNF overexpression significantly reduced tyrosine hydroxylase mRNA levels (by 39-72%) in the substantia nigra and ventral tegmental area neurons, and the optical density of tyrosine hydroxylase-immunoreactive innervation in the striatum was reduced by 25-52% with the most prominent reductions appearing caudally. No significant reduction was seen in striatal vesicular monoamine transporter 2-immunoreactivity or [3H]mazindole binding autoradiography to dopamine uptake sites, two other presynaptic markers in dopamine axon terminals. The striatal D1 and D2 receptor binding as determined by [3H]SCH23390 and [3H]spiperone binding, respectively, was unaltered relative to the intact side in both treatment groups. Preproenkephalin mRNA levels in postsynaptic striatal neurons, which increase upon removal of striatal dopamine, were also unaffected by the GDNF treatment. Taken together our findings indicate that sustained GDNF administration to intact nigrostriatal dopamine neurons selectively reduces tyrosine hydroxylase expression, without altering striatal dopamine transmission to the extent that compensatory changes in several other components related to dopamine storage and signalling occur.
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PMID:Long-term striatal overexpression of GDNF selectively downregulates tyrosine hydroxylase in the intact nigrostriatal dopamine system. 1254 62

Alpha-synuclein is a neuronal protein that is implicated in the control of synaptic vesicle function and in Parkinson's disease (PD). Consequently, alterations of alpha-synuclein levels may play a role in neurotransmission and in PD pathogenesis. However, the factors that regulate alpha-synuclein levels are unknown. Growth factors mediate neurotrophic and plasticity effects in CNS neurons, and may play a role in disease states. Here we examine the regulation of alpha-synuclein levels in primary CNS neurons, with particular emphasis on dopaminergic neurons. E18 rat cortical neurons and dopaminergic neurons of E14 rat ventral midbrain showed an induction of alpha-synuclein protein levels with maturation in culture. Application of basic Fibroblast growth factor (bFGF) promoted alpha-synuclein expression selectively within dopaminergic, and not GABAergic or cortical neurons. This induction was blocked by actinomycin D, but not by inhibition of bFGF-induced glial proliferation. alpha-Synuclein levels were not altered by glial-derived neurotrophic factor (GDNF), or by apoptotic stimuli. We conclude that bFGF promotes alpha-synuclein expression in cultured ventral midbrain dopaminergic neurons through a direct transcriptional effect. These results suggest that distinct growth factors may thus mediate plasticity responses or influence disease states in ventral midbrain dopaminergic neurons.
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PMID:Regulation of alpha-synuclein by bFGF in cultured ventral midbrain dopaminergic neurons. 1256 24

Nerve growth factor was the first identified protein with anti-apoptotic activity on neurons. This prototypic neurotrophic factor, together with the three structurally and functionally related growth factors brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and neurotrophin-4/5 (NT4/5), forms the neurotrophin protein family. Target T cells for neurotrophins include many neurons affected by neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and peripheral polyneuropathies. In addition, the neurotrophins act on neurons affected by other neurological and psychiatric pathologies including ischemia, epilepsy, depression and eating disorders. Work with cell cultures and animal models provided solid support for the hypothesis that neurotrophins prevent neuronal death. While no evidence exists that a lack of neurotrophins underlies the etiology of any neurodegenerative disease, these studies have spurred on hopes that neurotrophins might be useful symptomatic-therapeutic agents. However first clinical trials led to variable results and severe side effects were observed. For future therapeutic use of the neurotrophins it is therefore crucial to expand our knowledge about their physiological functions as well as their pharmacokinetic properties. A major challenge is to develop methods for their application in effective doses and in a precisely timed and localized fashion.
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PMID:Neurotrophins. 1257 26

Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor with restorative effects in a wide variety of rodent and primate models of Parkinson disease, but penetration into brain tissue from either the blood or the cerebro-spinal fluid is limited. Here we delivered GDNF directly into the putamen of five Parkinson patients in a phase 1 safety trial. One catheter needed to be repositioned and there were changes in the magnetic resonance images that disappeared after lowering the concentration of GDNF. After one year, there were no serious clinical side effects, a 39% improvement in the off-medication motor sub-score of the Unified Parkinson's Disease Rating Scale (UPDRS) and a 61% improvement in the activities of daily living sub-score. Medication-induced dyskinesias were reduced by 64% and were not observed off medication during chronic GDNF delivery. Positron emission tomography (PET) scans of [(18)F]dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, suggesting a direct effect of GDNF on dopamine function. This study warrants careful examination of GDNF as a treatment for Parkinson disease.
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PMID:Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. 1266 33

Transgenic technology, especially the use of homologous recombination to disrupt specific genes to produce knockout mice, has added considerably to the understanding of dopamine (DA) neuron develop, survival and function. The current review summarizes results from knockout mice with the target disruption of genes involved in the development of DA neurons (engrailed 1 and 2, lmx1b, and Nurr1), in maintaining DA neurotransmission (tyrosine hydroxylase, vesicular monoamine transporter, DA transporter, DA D2 and D3 receptors) and important for DA neuron survival (alpha-synuclein, glia cell line-derived neurotrophic factor and superoxide dismutase). As alterations in DA neurotransmission have been implicated in a number of human neuropathologies including Parkinson's disease, schizophrenia and attention deficit/hyperactivity disorder, understanding how specific genes are involved in the function of DA neurons and the compensatory changes that result from loss or reduction in gene expression could provide important insight for the treatment of these diseases.
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PMID:The control of dopamine neuron development, function and survival: insights from transgenic mice and the relevance to human disease. 1267 88

Possible cell death mechanisms for pars compacta nigro-striatal dopamine neurons in Parkinson's disease include oxidative stress, inflammatory processes, nitric oxide iron accumulation, glutamate toxicity and diminished neurotrophic factor responses. There is a notion that Parkinson's disease is not a single disorder but a syndrome that can be initiated by several factors. Because of limitations of biochemical methods in the global analysis of neuronal death, a full picture of events has not been established. However, recently developed cDNA microarray or microchips, in which the global expression of thousands of genes can be assessed simultaneously, is changing the prospect for understanding the disease process, its progression, response to drugs, etc. The neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is considered the most valid model of Parkinson's disease. We employed the technique of cDNA microarray gene expression to determine the mechanism of action of MPTP in mouse substantia nigra. Also, we studied neuroprotective processes induced by several compounds, including R-apomorphine and the green tea polyphenol epigallo-catechin-3-gallate (EGCG). This was done in two ways: (1) the time-dependent acute effect of MPTP, for determining which of the initial genes might lead to dopamine neuron death and (2) gene expression at the time of MPTP-induced dopamine neuron death. We observed that early (acute MPTP) gene expression differs from effects seen at the time of death (chronic MPTP), and that early gene changes are crucial for setting into action genes that eventually cause dopamine neuron death. Furthermore, this process is a cascade of "domino" effects, some of which were previously established by biochemical means. However, our findings show an additional large number of events previously unknown. The neuroprotective drugs reversed some but not all of the gene expression, suggesting involvement of these genes in the neurodegenerative process. Because of the profound complexity of "domino" effect it is now reasonable to understand why a single neuroprotective drug has not shown clinical neuroprotective efficacy. Future multi neuroprotective drugs may be necessary for treatment of not only Parkinson's disease, but other neurodegenerative diseases (e.g. Alzheimer's disease) and detrimental states (e.g. ischaemia).
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PMID:Early and late molecular events in neurodegeneration and neuroprotection in Parkinson's disease MPTP model as assessed by cDNA microarray; the role of iron. 1270 6

Epidemiologic studies revealed that the prevalence of Parkinson disease is higher in males than in females and that the progression of the disease might be rapid in males compared with females. The reason for the gender difference is unknown; however, estrogens may be involved. Many studies have revealed that estrogens provide neuroprotective effects and that the protective mechanisms include antioxidant property and upregulation of Bcl-2, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor (GDNF). Upregulation of Bcl-2 or GDNF is mediated by nonnuclear estrogen receptor (ER) in addition to transcription regulation by ER. To avoid undesirable effect of estrogens, several selective ER modulators, raloxifene and genistein are considered.
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PMID:Estrogens and Parkinson disease: novel approach for neuroprotection. 1277 6

Due to the development of molecular biology techniques, several types of neurotransmitter or neurotrophic factor secreting cell line can be established. These cell lines were grafted into the brain of animal models of Parkinson's disease and cerebral ischemia after encapsulating into the hollow fiber consisted of semipermeable membrane. Immunological reaction and tumor formation were prevented and functional effects were observed histologically, chemically and behaviorally. Current issues regarding encapsulated cell grafting are: delivery of neurotransmitter and neurotrophic factor simultaneously from one capsule, usage of human-derived cell lines and control of secretion from outside. There are two possible approaches regarding the usage of patient's own neural stem cells for regenerative therapy. Neural stem cells are collected from the subventricular zone of the lateral ventricle and these cells are differentiated into dopaminergic neurons using tyrosine hydroxylase induction cocktail (TH cocktail). Then, these neurons are grafted into the striatum of the patient. Another method is to inject TH cocktail into the patient's striatum in order to induce differentiation of dopaminergic neurons from the neural stem cells in vivo.
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PMID:[Intracerebral grafting of cell line or patient-derived neural stem cells for the treatment of neurological disorders]. 1278 89

We describe the discovery of a novel, 20 kDa, secreted human protein named mesencephalic astrocyte-derived neurotrophic factor, or MANF. The homologous, native molecule was initially derived from a rat mesencephalic type-1 astrocyte cell line and recombinant MANF subcloned from a cDNA encoding human arginine-rich protein. MANF selectively protects nigral dopaminergic neurons, versus GABAergic or serotonergic neurons. The discovery of MANF marks a more systematic approach in the search for astrocyte-derived, secreted proteins that selectively protect specific neuronal phenotypes. Compared to glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), MANF was more selective in the protection of dopaminergic neurons at lower (0.05-0.25 ng/mL) and middle (0.5-2.5 ng/mL) concentrations: MANF>GDNF>BDNF. GDNF was more selective at higher concentrations (25-50 ng/ml): GDNF>MANF>BDNF. Two domains in MANF of 39-AA and 109-AA respectively, and eight cysteines are conserved from C. elegans to man. MANF is encoded by a 4.3 Kb gene with 4 exons, and is located on the short arm of human chromosome 3. The secondary structure is dominated by alpha-helices (47%) and random coils (37%). Studies to determine the localization of MANF in the brains of rat, monkey, and man, as well as the receptor, signaling pathways, and biologically active peptide mimetics are in progress. The selective, neuroprotective effect of MANF for dopaminergic neurons suggests that it may be indicated for the treatment of Parkinson's disease.
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PMID:MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons. 1279 11


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