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)

In mice carrying the weaver mutation there is a spontaneous degeneration of dopaminergic neurons that is heterogeneous among cell groups: nigrostriatal neurons are more affected than mesolimbic neurons, while involvement of the mesocortical system is controversial. We questioned whether the pattern of cell loss in mesencephalon and fiber depletion in telencephalon could be related to the differential content of Calbindin-D28k in dopaminergic cells. The mesencephalon of seven-month-old mutants was serially sectioned and alternate series were immunostained with tyrosine hydroxylase and Calbindin-D28k. Cell counts indicated a 40% loss for the ensemble of dopamine mesencephalic neurons. However, double-immunostained preparations revealed that this cell loss was restricted to the neurons that lacked Calbindin-D28k, which were reduced by 72%, while the dopaminergic neurons containing Calbindin-D28k were completely spared. Calbindin-D28k was present in both the cytoplasm and nucleus of the dopaminergic cells. This nuclear localization was confirmed at the ultrastructural level. In the telencephalon of weaver mutants, areas receiving projections from the Calbindin-D28k-positive dopaminergic neurons, such as the cerebral cortex, contained normal densities of fibers, while areas harboring projections from the non-Calbindin-D28k dopaminergic neurons, such as the dorsal striatum, had reduced amounts of fibers. The vulnerability pattern in the mesencephalon of weaver mutants bears similarities to that described in idiopathic Parkinson's disease or in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism: Calbindin-D28k may thus delimit a group of dopaminergic neurons resistant to cell death in different conditions. On the other hand, the vulnerability pattern of dopaminergic fibers in weaver differs from that of Parkinson's disease, since there is a complete sparing of the dopaminergic mesocortical projection in weaver, contrasting with the damage of these projections in Parkinson's disease.
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PMID:Sparing of the dopaminergic neurons containing calbindin-D28k and of the dopaminergic mesocortical projections in weaver mutant mice. 796 10

In this study, calbindin D-28k (CaBP), monoamine oxidase A (MAO A) and nerve growth factor receptor (NGFr) immunoreactivities were investigated in the nucleus basalis of Meynert (NbM) in patients with senile dementia of the Alzheimer type (SDAT), with Parkinson's disease (PD) with or without dementia, and in controls. Immunocytochemistry using specific antibodies in differing serial sections was employed, and cell counts and NbM nuclear volume measurements were made. Most of the large multipolar NbM neurons showed CaBP immunoreactivity in the cytoplasm of their somata, dendrites and axons. In adjacent, NGFr-reacted sections, the large NbM neurons were also found to be intensely immunoreactive for NGFr on their cellular surfaces. In addition, a subpopulation of large NbM neurons and glial cells were found to be immunoreactive for MAO A. The number of CaBP-immunoreactive (CaBP-i) neurons was decreased by an average of 55% in the 6 SDAT patients, 70% in the 2 nondemented PD patients and 40% in the 1 demented PD patient. The volume calculated for the compact part of the NbM formed by the CaBP-i neuronal somata decreased by an average of 47% in SDAT. On the other hand, measurements in the volume of NGFr-i neurons (including the dendritic arborization) showed an average decrease of 25% in SDAT patients compared to controls. Although all SDAT and PD patients showed a decrease of CaBP-i neurons in the NbM, a loss of MAO-A-i NbM neurons was found only in those patients with dementia. Therefore, the relative proportions of MAO-A-i to CaBP-i neurons were increased in the nondemented PD patients (14.2 and 19.6%) when compared with those in the demented PD patient (2.2%) and with the SDAT patients (0.3-5.6%). These data indicate that a balanced presence of MAO-A-i cholinergic, large NbM neurons may be necessary for the proper maintenance of cognitive function. Functionally this may be translated to mean that dementing changes may cause a decrease from the normal amount of MAO A enzyme activity. This suggests that therapeutic strategies based upon correction of MAO-A activities by MAO-A inhibitors may be important to ameliorating some of the loss in cholinergic function in dementias of SDAT and PD.
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PMID:Calbindin D-28k and monoamine oxidase A immunoreactive neurons in the nucleus basalis of Meynert in senile dementia of the Alzheimer type and Parkinson's disease. 835 1

Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra and, to a lesser extent, the ventral tegmental area and catecholaminergic cell group A8. However, among these dopaminergic neurons, those expressing the calcium buffering protein calbindin are selectively preserved, suggesting that a rise in intracellular calcium concentrations may be involved in the cascade of events leading to nerve cell death in Parkinson's disease. We therefore analysed immunohistochemically the expression of the calcium-dependent protease calpain II (m-calpain) in the mesencephalon of patients with Parkinson's disease, progressive supranuclear palsy or striatonigral degeneration, where nigral dopaminergic neurons degenerate, and matched controls without nigral involvement. Calpain immunoreactivity was found in fibers and neuronal perikarya in the substantia nigra, the ventral tegmental area, catecholaminergic cell group A8 and the locus coeruleus. In patients with Parkinson's disease but not with the other neurodegenerative disorders, m-calpain immunoreactivity was detected in fibers with an abnormal morphology and in Lewy bodies. Sequential double staining revealed that most of these m-calpain-positive fibers and neuronal perikarya co-expressed tyrosine hydroxylase, indicating that most m-calpain neurons are catecholaminergic. Quantitative analysis of m-calpain staining in the substantia nigra and locus coeruleus revealed an increased density of fibers and neuronal perikarya in parkinsonian patients in both structures. These data suggest that increased calcium concentrations may be associated with nerve cell death in Parkinson's disease.
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PMID:Increased M-calpain expression in the mesencephalon of patients with Parkinson's disease but not in other neurodegenerative disorders involving the mesencephalon: a role in nerve cell death? 880 17

Calbindin-D28k is a calcium-binding protein that protects nerve cells from degeneration. It is located in the midbrain dopaminergic neurons that are relatively invulnerable to degeneration in Parkinson's disease. Because the hypothalamic dopaminergic neurons do not degenerate in Parkinson's disease, the present study sought to determine whether these neurons also contain calbindin-D28k. Using immunocytochemical staining with antibodies against calbindin-D28k and tyrosine hydroxylase, and computer imaging techniques, the distributions of calbindin-D28k and tyrosine hydroxylase-containing neurons were mapped. Both neuronal populations were present throughout the rostral-caudal extent of the hypothalamus. However, only in the periventricular region, at the preoptic and anterior hypothalamic levels, was there an overlap in the two cellular distributions. Using the presence of neuromelanin pigment as a marker for dopaminergic neurons, approximately 30% of the dopaminergic neurons contain calbindin-D28k in the periventricular region. These data indicate that a sub-population of hypothalamic dopaminergic neurons contain calbindin-D28k. This finding is discussed in terms of why hypothalamic dopaminergic neurons are resistant to degeneration in Parkinson's disease.
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PMID:Calbindin-D28k-containing neurons in the human hypothalamus: relationship to dopaminergic neurons. 884 30

The calcium-binding proteins Calbindin-D28k and calretinin are co-localized with dopamine in some of the midbrain dopaminergic neurons in the rat and monkey; the present study sought to examine the pattern of co-localization in the mouse. Double immunofluorescence staining procedures were used for tyrosine hydroxylase (a dopaminergic cell marker) and Calbindin-D28k or calretinin. Midbrain dopaminergic neurons were examined at four rostrocaudal levels, and the percentage of cells that contained both tyrosine hydroxylase and either of the two calcium-binding proteins was determined in nucleus A8 (retrorubral field), nucleus A9 (substantia nigra pars compacta, pars reticulata and pars lateralis) and nucleus A10 (nucleus paranigralis, ventral tegmental area, interfascicular nucleus, central linear nucleus). The two calcium-binding proteins were distributed similarly in midbrain dopaminergic neurons in the several nuclear groups that comprise nuclei A8, A9 and A10. The calcium-binding proteins were found in the majority (50-100%) of nucleus A10 neurons, whereas in nuclei A8 and A9 (except for the substantia nigra pars lateralis) less than 40% of the cells contained either calcium-binding protein. The pattern of co-localization in the mouse is similar to that reported for the rat and monkey. The calcium-binding proteins mark the population of midbrain dopaminergic neurons that are less vulnerable to degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.
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PMID:Midbrain dopaminergic neurons in the mouse: co-localization with Calbindin-D28K and calretinin. 893 Oct 15

Calbindin-D28k (calbindin) is an intracellular calcium binding protein of unknown in vivo function. It is abundantly expressed in many populations of neurons, and it can, presumably by buffering calcium overload, protect cells against excitotoxic damage. In the midbrain, calbindin is preferentially expressed in those dopamine neurons which are spared from degeneration in Parkinson's disease and its animal models. Whether calbindin itself determines neuronal vulnerability is questioned in other lesion models where calbindin expression is not positively correlated with neuronal resistance. To study the possible neuroprotective role of calbindin in vivo, we generated calbindin-deficient mice by gene targeting and assessed the viability of midbrain dopamine neurons in both a chemical and a genetic lesion paradigm. Tyrosine hydroxylase-immunoreactive neurons were counted in calbindin null-mutant mice treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and in a calbindin-deficient weaver strain (homozygous for weaver and the calbindin null mutation). The extent and pattern of neuron loss observed in MPTP-treated wild-type and homozygous weaver mice were as previously described. Surprisingly, no significant differences were observed between MPTP-treated calbindin null mutants and their wild-type littermates, or between calbindin-weaver double mutant mice and weaver mice. Thus, in all four groups the same subpopulation of tyrosine hydroxylase-positive midbrain neurons (i.e. those normally containing calbindin) were preferentially spared. Calretinin, a closely related calcium-binding protein, which is also expressed in some midbrain dopamine neurons, was not up-regulated in these surviving neurons. These findings indicate that the resistance of calbindin-containing neurons in the MPTP and weaver models is not causally related to the expression of calbindin, and that endogenous calbindin is not required for protection of these neurons.
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PMID:Vulnerability of midbrain dopaminergic neurons in calbindin-D28k-deficient mice: lack of evidence for a neuroprotective role of endogenous calbindin in MPTP-treated and weaver mice. 904 76

The calcium-binding protein calbindin-D28k (CB) is located in midbrain dopaminergic (DA) neurons that are less vulnerable to degeneration in Parkinson's disease and in an animal model of the disorder, the MPTP-treated monkey. The present study sought to determine whether CB-containing DA neurons are also less vulnerable to degeneration in the MPTP-treated mouse. Double-labelling immunocytochemical staining and computer imaging techniques were employed to map and quantify the tyrosine hydroxylase-, CB- and CB-containing tyrosine hydroxylase neurons in portions of nucleus A9 and nucleus A10 (ventral tegmental area and central linear nucleus) following MPTP treatment in the C57BL/6 mouse. A cumulative dose of 140 mg/kg MPTP produced a significantly greater loss of DA neurons that lack CB in both nucleus A9 (71 +/- 4%) and the ventral tegmental area (70 +/- 4%), compared to the loss of DA neurons that contain CB (44 +/- 6% and 25 +/- 14%, respectively). In the central linear nucleus there was no loss of CB-containing DA neurons. These data demonstrate that the presence of CB in midbrain DA neurons identifies a population of cells in the mouse that are less vulnerable to MPTP-induced degeneration. The mouse, therefore, can serve as a useful model in which to investigate the putative neuroprotective effects of CB in an animal model of Parkinson's disease.
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PMID:Midbrain dopaminergic neurons in the mouse that contain calbindin-D28k exhibit reduced vulnerability to MPTP-induced neurodegeneration. 911 42

The neurotoxin MPTP kills only certain midbrain dopaminergic (DA) neurons to produce a model of Parkinson's disease. The dopamine transporter (DAT) is important to MPTP toxicity because to be neurotoxic, an MPTP metabolite must first gain access to the DA neuron via the DAT. Also, MPTP is less toxic to DA neurons that contain the putative neuroprotective calcium-binding protein calbindin-D28k (CB). The present study examined the relative importance of DAT activity and CB for cellular vulnerability to MPTP-induced degeneration in the C57BL/6 mouse. Cells that were vulnerable to MPTP were found to contain high levels of DAT mRNA, whereas cells that were not vulnerable contained low levels. Also, the few substantia nigra cells remaining after a toxic dose of MPTP contained only low levels of DAT mRNA. However, there was not a strong relationship between cellular resistance to MPTP toxicity and cells containing CB. These data provide in vivo evidence for a direct correlation between midbrain cellular vulnerability to MPTP toxicity and the activity of the DAT.
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PMID:Dopamine transporter mRNA levels are high in midbrain neurons vulnerable to MPTP. 935 66

Neuronal damage in certain cellular populations in the brain has been linked to oxidative stress accompanied by an elevation in intracellular calcium. Many questions remain about how such oxidative stress occurs and how it affects calcium homeostasis. Glutathione (GSH) is a major regulator of cellular redox status in the brain, and lowered GSH levels have been associated with dopaminergic cell loss in Parkinson's disease (PD). We found that transfection of antisense oligomers directed against glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH synthesis, into PC12 cells resulted in decreased GSH and increased levels of ROS. Decreased GSH levels also correlated with an increase in intracellular calcium levels. Data from this study suggest that dopaminergic neurons are very sensitive to decreases in the internal oxidant buffering capacity of the cell caused by reductions in GSH levels, and that alterations in this parameter can result in disruption of calcium homeostasis and cell death. These results may be of particular significance for therapeutic treatment of PD, as those dopaminergic neurons that are spared in this disorder appear to contain the calcium binding protein, calbindin.
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PMID:Decreased glutathione results in calcium-mediated cell death in PC12. 935 49

The calcium-binding protein calbindin-D28k (CB) has been hypothesized to function, in part, as a neuroprotective protein. CB is localized within nerve cells that are often less vulnerable to degeneration in patients with Alzheimer's disease and Parkinson's disease, and cells containing CB can buffer intracellular calcium concentrations ([Ca2+]i). The present study was designed to directly test the hypothesis that CB can protect cells from degeneration by reducing [Ca2+]i. PC12 cells, transfected to express different levels of CB, were found to be significantly less vulnerable to degeneration caused by serum withdrawal, glutamate, and the neurotoxin 1-methyl-4-phenylpyridinium (MPP+). However, CB did not protect cells from degeneration caused by the calcium ionophore A23187. CB-transfected cells exhibited reduced elevations in [Ca2+]i following treatment with bradykinin, or ATP compared to non-CB-containing cells. These data indicate that CB can protect cells from degeneration caused by certain conditions, and it reduces elevations in [Ca2+]i caused by influx from extracellular sources.
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PMID:Calbindin-D28k buffers intracellular calcium and promotes resistance to degeneration in PC12 cells. 952 44


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