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)

Unusual cytoskeleton abnormalities were found in the brains of 28 individuals afflicted with adult onset dementia. Most conspicuous were small spindle-shaped argyrophilic grains loosely scattered throughout the neuropil. Additionally, coiled bodies of silver-stained filaments were encountered, mainly located within the white matter close to the cortical grey matter. Argyrophilic grains and coiled bodies contained dense accumulations of straight filaments with a diameter of about 9 nm. The argyrophilic grains were found in abundance within sector CA1 of the Ammon's horn and layer Pre-beta of the entorhinal region. A slightly less dense scattering of the grains occurred in layer IIIab of the adjoining temporal isocortex, insular cortex and orbitofrontal cortex. The basolateral amygdaloid complex and the hypothalamic lateral tuberal nucleus were the most affected subcortical structures. Deeper brain stem nuclei merely showed a sparse number of grains or were devoid of them. Eighty brains of demented individuals were examined. Forty-eight of them showed the features of Alzheimer's disease and four showed the features of Pick's disease. Twenty-eight cases revealed the abnormalities under consideration. Ten showed exclusively argyrophilic grains and coiled bodies, while 16 also had neuritic plaques, neurofibrillary tangles, and neuropil threads. One of the 28 cases was associated with Parkinson's disease and one showed features of both Parkinson's and Alzheimer's disease. Twenty brains of non-demented individuals of about the same age and devoid or almost devoid of Alzheimer changes were used as controls. None of the control brains showed the presence of argyrophilic grains and coiled bodies. These changes, therefore, are considered the morphological substrate of an unknown disease associated with adult onset dementia.
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PMID:Cortical and subcortical argyrophilic grains characterize a disease associated with adult onset dementia. 247 Nov 9

Ubiquitin has previously been identified as a component of neuronal inclusions in neurodegenerative disorders. In this investigation, we examined tissue from cases of Alzheimer's disease (AD), Pick's disease, Parkinson's disease (PD), and progressive supranuclear palsy (PSP) to identify previously unrecognized ubiquitinated structures and to assess the evolution of neuronal inclusions. In AD, approximately 60% of neurofibrillary tangles (NFTs) that were stained with an anti-paired helical filaments (PHF) serum were identified by the ubiquitin antibodies. Extracellular NFTs were not labelled with anti-PHF but were unlabelled or weakly labelled with anti-ubiquitin antibodies. In Pick's disease, most Pick bodies were strongly labelled by the ubiquitin antibodies, and in addition some hippocampal CA1 neurones contained granular or strand-like ubiquitin-immunoreactive (IR) inclusions associated with more typical Pick bodies. Typical Lewy bodies in PD cases showed an unlabelled central core with an outer ring intensely labelled by ubiquitin antibodies. Pale bodies in pigmented substantia nigra neurones appeared as large well-defined, rounded structures without an identifiable core or peripheral zone. Some pale bodies were unlabelled by ubiquitin antibodies, but others showed labelling of variable intensity. Pale bodies which were labelled by ubiquitin antibodies tended also to be labelled by BF10, a monoclonal antibody against phosphorylated neurofilaments. We suggest that pale bodies in PD may represent stages in the formation of Lewy bodies. In addition, we observed numerous spindle-shaped ubiquitin-IR swellings of dendrites of pigmented substantia nigra neurones. In contrast to inclusions of AD and Pick's disease, the PHF-positive fibrillary neuronal inclusions of PSP were either unlabelled or only weakly labelled by ubiquitin antibodies. No ubiquitinated structures were seen in neurones from corresponding areas in aged controls. Identification of ubiquitinated proteins in neurodegenerative disorders may provide insights into molecular events associated with cell death.
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PMID:New aspects of the pathology of neurodegenerative disorders as revealed by ubiquitin antibodies. 255 99

Bromocriptine, a dopamine D2 receptor agonist, has widely been used for patients with Parkinson's disease. In this study, we examined its neuroprotective effects against neuronal damage in the CA1 subfield of the hippocampus following experimental cerebral ischemia in the Mongolian gerbil. Forebrain ischemia was induced by occlusion of bilateral common carotid arteries for 3 min. Bromocriptine, at a dose of 0.3 or 3 mg/kg, was injected i.p. 30 min before the onset of ischemia. Histopathological observations showed that neuronal damage to hippocampal CA1 neurons, which was seen 7 days after ischemia in vehicle-treated animals, was prevented by bromocriptine treatment. Immunohistochemical staining for copper/zinc superoxide dismutase and manganese superoxide dismutase decreased markedly in the CA1 neurons of vehicle-treated animals 2 days after ischemia when histological neuronal destruction was not yet seen, but was well preserved in bromocriptine-treated animals. The present findings show that bromocriptine protects against ischemia-induced neuronal damage, and that the mechanism of the neuroprotection may relate to the preservation of SODs. Bromocriptine, which was recently shown to be a potent free radical scavenger, may have a potent neuroprotective action against disorders including ischemic stroke.
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PMID:Bromocriptine protects against delayed neuronal death of hippocampal neurons following cerebral ischemia in the gerbil. 775 51

Transgenic (NFHLacZ) mice expressing a fusion protein composed of a truncated high-molecular-weight mouse neurofilament (NF) protein (NFH) fused to beta-galactosidase (LacZ) develop inclusions in neurons throughout the CNS. These inclusions persist from birth to advanced age and contain massive filamentous aggregates including all three endogenous NF proteins and the NFHLacZ fusion protein. Further, the levels of endogenous NF proteins are selectively reduced in NFHLacZ mice. Because these inclusions resemble NF-rich Lewy bodies (LBs) in Parkinson's disease and LB dementia, we asked whether these lesions compromised the viability of affected neurons during aging. We studied hippocampal CA1 neurons, nearly all of which harbored inclusions (type I) devoid of cellular organelles, and cerebellar Purkinje cells, nearly all of which accumulated inclusions (type II) containing numerous entrapped organelles. Purkinje cells with type II inclusions began to degenerate in the NFHLacZ mice at approximately 1 year of age, and most were eliminated by 18 months of age. In contrast, there was no significant loss of type I inclusion-bearing CA1 neurons with age. These data suggest that the sequestration of cellular organelles in type II inclusions may isolate and impair the function of these organelles, thereby rendering Purkinje cells selectively vulnerable to degeneration with age as in neurodegenerative diseases of the elderly characterized by accumulation of LBs.
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PMID:Selective degeneration fo Purkinje cells with Lewy body-like inclusions in aged NFHLACZ transgenic mice. 899 61

Severe dementia affects 10 to 20% of all patients with Parkinson's disease (PD) and is particularly common in those aged 65 years and over. In a clinicopathologic study, we correlated Mini-Mental State Examination scores and DSM-III dementia ratings with the density of Lewy bodies, Lewy neurites, neurofibrillary tangles, neuritic plaques, gliosis, and neurons in the hippocampus and amygdala of 27 PD patients without Alzheimer's disease changes. Cortical Lewy body densities were examined in the anterior cingulate gyrus. The degree of cognitive impairment was correlated with the density of Lewy neurites in the CA2 hippocampal field, raising the possibility that disruption of the connection between the dentate gyrus, entorhinal cortex, septal nuclei, and hypothalamus and the CA1 field contributes to dementia in PD.
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PMID:The relationship between dementia and direct involvement of the hippocampus and amygdala in Parkinson's disease. 981 13

alpha-Synuclein (alphaSN), also termed the precursor of the non-Abeta component of Alzheimer's disease (AD) amyloid (NACP), is a major component of Lewy bodies and Lewy neurites pathognomonic of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). A fragment of alphaSN termed the non-Abeta component of AD amyloid (NAC) had previously been identified as a constituent of AD amyloid plaques. To clarify the relationship of NAC and alphaSN with Abeta plaques, antibodies were raised to three domains of alphaSN. All antibodies produced punctate labeling of human cortex and strong labeling of Lewy bodies. Using antibodies to alphaSN(75-91) to label cortical and hippocampal sections of pathologically proven AD cases, we found no evidence for NAC in Abeta amyloid plaques. Double labeling of tissue sections in mixed DLB/AD cases revealed alphaSN in dystrophic neuritic processes, some of which were in close association with Abeta plaques restricted to the CA1 hippocampal region. In brain homogenates alphaSN was predominantly recovered in the cytosolic fraction as a 16-kd protein on Western analysis; however, significant amounts of aggregated and alphaSN fragments were also found in urea extracts of SDS-insoluble material from DLB and PD cases. NAC antibodies identified an endogenous fragment of 6 kd in the cytosolic and urea-soluble brain fractions. This fragment may be produced as a consequence of alphaSN aggregation or alternatively may accelerate aggregation of the full-length alphaSN.
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PMID:Non-Abeta component of Alzheimer's disease amyloid (NAC) revisited. NAC and alpha-synuclein are not associated with Abeta amyloid. 1066 11

Although neural transplantation has made a relatively successful transition from the animal laboratory to human neurosurgery for the treatment of Parkinson's disease, the use of human embryonic brain tissue as the source of transplants raises difficult ethical and practical problems. These are likely to impede the widespread use of this otherwise promising therapy across the range of types of brain damage to which the results of animal experiments suggest its potential applicability. Various alternative approaches are reviewed briefly, aimed at developing sources of tissue for transplantation that can be maintained in vitro until needed, so obviating the requirement for fresh embryonic tissue at each occasion of surgery. Particularly promising are conditionally immortalized neuroepithelial stem cell lines in which the immortalizing gene is downregulated upon transplantation into a host brain. We describe experiments from our laboratory with the use of cells of this kind, the multipotent MHP clonal cell lines, derived from the developing hippocampus of a transgenic mouse harbouring a temperature-sensitive oncogene. Implanted into the hippocampus of rats and marmosets with damage to the CA1 cell field, the MHP36 line gave rise to healthy surviving grafts and to essentially complete recovery of cognitive function. Postmortem study of the implanted rat brains indicated that MHP36 cells migrate to the region of damage, adopt both neuronal (pyramidal) and glial phenotypes in vivo, and reconstitute the normal laminated appearance of the CA1 cell field. We have previously shown that, when primary differentiated foetal tissue is used as the source of grafts in rats with CA1 damage, there is a stringent requirement for replacement with homotypic CA1 cells. We interpret our results as showing that the MHP36 cell line responds to putative signals associated with damage to the hippocampus and takes up a phenotype appropriate for the repair of this damage; they therefore open the way to the development of a novel strategy with widespread applicability to the treatment of the diseased or damaged human brain.
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PMID:Prospects for the clinical application of neural transplantation with the use of conditionally immortalized neuroepithelial stem cells. 1051 1

In several neurodegenerative diseases, iron accumulates at sites of brain pathology. Since post-mortem examination cannot distinguish whether iron accumulation caused the damage or resulted from damage, it is necessary to manipulate iron in animal and tissue culture models to assess its causal role(s). However, only in models of Parkinson's disease and of global ischemia, iron deprivation (ID) or iron-chelators have been used to protect from damage. In these studies, documentation of microgliosis was not performed even though several lines of evidence converge to suggest that activation of microglia is an important source of oxidative stress. In the kainate model of epilepsy, we found that ID protected the olfactory cortex, thalamus and hippocampus and attenuated microgliosis, whereas iron supplementation to ID rats increased damage and microgliosis in the above regions. In the hilus of the hippocampal dentate gyrus, even though no cell loss was observed, ID attenuated microgliosis and iron-supplementation increased it. Thus there is a tight relationship between iron and microgliosis. In addition, iron+zinc supplementation dramatically increased damage to hippocampal CA1 whereas zinc supplementation alone had no effect. This study demonstrates an anatomically unique interaction of iron and zinc, which may lead to new insights to neurodegeneration in epilepsy.
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PMID:Iron involvement in neural damage and microgliosis in models of neurodegenerative diseases. 1087 37

Approval to commence phase I/II clinical trials with neural stem cells requires proof of concept in well-accepted animal models of human neurological disease or injury. We initially showed that the conditionally immortal MHP36 line of hippocampal origin (derived from the H-2Kb-tsA58 transgenic mouse) was effective in repopulating CA1 neurons in models of global ischaemia and repairing cognitive function, and have now shown that this line is multifunctional. MHP36 cells are effective in restoring spatial memory deficits in rats after excitotoxic lesions of the cholinergic projections to cortex and hippocampus and in rats showing cognitive impairments due to normal ageing. Moreover, grafts of MHP36 cells are effective in reversing sensory and motor deficits and reducing lesion volume as a consequence of occlusion of the middle cerebral artery, the major cause of stroke. In contrast, MHP36 cell grafts were unable to repair motor asymmetries in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopamine system, the prototype rodent model of Parkinson's disease. These data show that conditionally immortal neuroepithelial stem cells are multifunctional, being able to repair diverse types of brain damage. However, there are limitations to this multifunctionality, suggesting that lines from different regions of the developing brain will be required to treat different brain diseases. ReNeuron is currently developing human neuroepithelial stem cell lines from different brain regions and with similar reparative properties to our murine lines.
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PMID:Functional repair with neural stem cells. 1113 43

Cynomolgus monkeys (Macaca fascicularis) were chronically treated with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) until stable parkinsonism was reached. Two months later, monkeys were sacrificed and monoamine content was measured in different brain regions of the lesioned monkeys and of age-matched controls. 5-HT(1A) serotonin receptor density was measured in coronal sections labeled with [(3)H]8-OH-DPAT. As expected, dopamine was virtually nonexistent in the caudate nucleus and putamen of MPTP-treated monkeys. Serotonin levels were significantly reduced in different brain regions, particularly in the raphe nuclei. 5-HT(1A) receptor density of control animals was high in the hippocampus, notably in the CA1 field and also in the raphe nuclei, and much lower in the striatum, where 5-HT(1A) receptors showed a patchy distribution which corresponded to striosomes with poor calbindin immunostaining. 5-HT(1A) receptor density was reduced in hippocampal fields and in the raphe nuclei of parkinsonian monkeys. Conversely, in the severely lesioned striatal nuclei 5-HT(1A) receptor density was increased at caudal levels of the striatum, particularly in the putamen. The results tend to support the possibility of an increased synthesis of 5-HT(1A) receptors in brain regions with higher neuronal cell death. Upregulation of this 5-HT receptor subtype in the limbic compartment of the striatum may represent a compensatory event for the serotonergic dysfunction and associated mental disorders in neurodegenerative diseases such as Parkinson disease.
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PMID:Serotonin 5-HT(1A) receptor expression is selectively enhanced in the striosomal compartment of chronic parkinsonian monkeys. 1116 78


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