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)

A number of chronic degenerative disorders including cerebellar astrocytomas and Parkinson's disease are characterized by the presence of cytosolic inclusions which contain intermediate filament (IF) aggregates and ubiquitin-protein conjugate immunoreactivity. In cerebellar astrocytomas these inclusions are known as Rosenthal fibres. 2,5-hexanedione (HD) treatment is known to induce IF aggregates in cells in culture. HD-induced aggregates have therefore been studied as a potential model for the clinical inclusions. Exposure of astrocyte cultures to 2 mM HD for 2 or 4 weeks led to the formation of aggregates of the IFs (glial fibrillary acidic protein and vimentin). The aggregates contained ubiquitin-protein conjugates, which, on electron microscopy appeared to be localized in a peripheral shell. In addition, ubiquitin mRNA levels were found to be elevated approximately threefold by HD treatment. HD-induced inclusions and Rosenthal fibres were found to share a number of features. HD administration, therefore, appears to be a suitable model for the production of pathological inclusions.
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PMID:2,5-Hexanedione-induced intermediate filament aggregates contain ubiquitin-protein conjugate immunoreactivity and resemble Rosenthal fibres. 133 14

Vimentin immunoreactivity was examined in brain tissues from non-neurological and various human central nervous system disease cases. In all brain tissues examined, vimentin immunoreactivity was intensely positive in ependymal cells and subpial tissues, and weakly positive in some capillaries and some white matter astrocytes. In affected areas of Alzheimer's disease (AD), Pick's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and cerebral infarction cases, numerous intensely vimentin-immunopositive astrocytes of both protoplasmic and fibrous morphology were demonstrated. A few such astrocytes were also observed in Parkinson's disease and progressive supranuclear palsy. ALS, MS and infarction brains also had numerous, strongly vimentin-positive, round and fat-laden microglia/macrophages. In AD and ALS, a few reactive microglia with irregularly enlarged shapes were vimentin positive. In AD, they were almost exclusively related to senile plaques.
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PMID:Vimentin immunoreactivity in normal and pathological human brain tissue. 152 71

We have recently shown that there is a previously unsuspected link between the intracellular inclusions seen in several major chronic human degenerative diseases, including neurodegenerative diseases: the inclusions showing ubiquitin immunoreactivity. The conditions include Parkinson's disease, motor neurone disease, Alzheimer's disease, Pick's disease, and alcoholic liver disease as well as cerebellar astrocytomas and a myopathy. The inclusions found in these diseases are reported to contain intermediate filaments: neurofilaments are associated with Lewy bodies in Parkinson's disease, Pick's bodies in Pick's disease and neurofibrillary tangles in Alzheimer's disease, cytokeratins are found in Mallory bodies in alcoholic liver disease, glial fibrillary acidic proteins and vimentin are found in Rosenthal fibres in astrocytomas, and desmin is found in cytoplasmic bodies in cytoplasmic body myopathy. Therefore five classes of intermediate filaments are found in inclusions which also contain ubiquitin immunoreactivity; we have also shown that ubiquitin immunoreactivity is present in vesicles in some areas of granulovacuolar degeneration in Alzheimer's disease. Protein ubiquitination is considered a signal for extralysosomal protein degradation, (although ubiquitination may have several other important functions). We have recently shown that intermediate filaments are involved in protein sequestration before degradation by lysosomally mediated autophagy: therefore intermediate filament-containing ubiquitinated inclusions may be the hallmarks of cellular attempts to eliminate pathogenic insults by the activation of both extralysosomal and lysosomal mechanisms of intracellular protein degradation. We have recently been able to reproduce, at least in part, some of the clinical observations in tissue culture cells. Ubiquitinated protein conjugates accumulate in lysosomes in fibroblasts treated with the lysosomal cysteine protease inhibitor E-64, which may mimic aspects of granulovacuolar degeneration.
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PMID:Intermediate filaments and ubiquitin: a new thread in the understanding of chronic neurodegenerative diseases. 255 42

A primary neuronal culture was prepared from the ventral mesencephalon, centered on the A8, A9 and A10 dopaminergic nuclei of the embryonic day 14 rat, and studied from 12 h to 28 days. At 12 h after plating, and before cell death ensued, 95% of the cells stained positive for neuron specific enolase; 20% for tyrosine hydroxylase; 5% for vimentin and < 0.1% for glial fibrillary acidic protein. In the presence of the mitotic inhibitor cytosine arabinoside (2.0 microM), neuronal growth and survival were surprisingly normal up to the ninth day in culture, but deteriorated rapidly thereafter. In the absence of a mitotic inhibitor, and in the presence of proliferating but non-confluent glia, the tyrosine hydroxylase positive neurons that survived to the 10th day, had retracted neurites and a rounded soma, suggesting an inhibition of cell development. Those tyrosine hydroxylase positive neurons that survived this adverse phase of development tended to produce elaborate neuritic profiles after the 11th day, coincident with confluence of the astrocyte monolayer at the 12th day. By the 21st day in culture, and persisting up to the 28th day, 60% (61 +/- 10, n = 20) of the surviving neurons stained positive for tyrosine hydroxylase. When plated on an established, ventral mesencephalic monolayer of astrocytes, at the seventh day in culture, neuritic growth and branching of the tyrosine hydroxylase positive neurons were greater, compared with similar neurons grown on poly-D-lysine, and the signs of arrested development (retraction of neurites and rounded soma) seen at the 10th day after plating on poly-D-lysine, were not observed. We conclude that in the primary culture studied, and under the experimental conditions used, the survival of dopaminergic neurons was independent of glia during the first nine days, and critically dependent on glia thereafter. The resurgence of growth of dopaminergic neurons after 10 days in vitro, and their subsequent selective survival in culture, suggest that confluent type-1 astrocytes produce factors that act selectively on the dopaminergic neuronal phenotype. The successful identification of these dopaminergic-specific, neurotrophic factors could lead to an increased understanding of the etiology of Parkinson's disease, and suggest new directions for therapeutic intervention.
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PMID:Astrocyte-dependent and -independent phases of the development and survival of rat embryonic day 14 mesencephalic, dopaminergic neurons in culture. 793 1

The use of primary human fetal tissue in the treatment of neurodegenerative disorders, while promising, faces several difficult technical and ethical issues. An alternative approach that would obviate these problems would be to use immortalized cell lines of human fetal central nervous system origin. An immortalized human fetal astrocyte cell line (SVG) has been established (45) and herein we describe the in vitro and in vivo characteristics of this cell line which suggest that it may be a useful vehicle for neural transplantation. The SVG cell line is vimentin, GFAP, Thy 1.1 and MHC class I positive, and negative for neurofilament and neuron specific enolase, consistent with its glial origin. To determine whether the cell line could be used as a drug delivery system, a cDNA expression vector for tyrosine hydroxylase was constructed (phTH/Neo) and stably expressed in the SVG cells for over 18 months as demonstrated by immunohistochemistry and Western blotting of the stable transfectants. HPLC analysis of the supernatant from these cells, termed SVG-TH, consistently found 4-6 pmol/ml/min of l-dopa produced with the addition of BH4 to the media. Furthermore, in cocultivation experiments with hNT neurons, PC-12 cells and primary rat fetal mesencephalic tissue, both the SVG and SVG-TH cells demonstrated neurotrophic potential, suggesting that they constituitively express factors with neuroregenerative potential. To determine the viability of these cells in vivo, SVG-TH cells were grafted into the striatum of Sprague-Dawley rats and followed over time. A panel of antibodies was used to unequivocally differentiate the engrafted cells from the host parenchyma, including antibodies to: SV40 large T antigen (expressed in the SVG-TH cells), human and rat MHC class 1, vimentin, GFAP, and tyrosine hydroxylase. While the graft was easily identified with the first week, over the course of a four week period of time the engrafted cells decreased in number. Concomittantly, rat CD4 and CD8 expression in the vicinity of the graft increased, consistent with xenograft rejection. When the SVG-TH cells were grafted to the lesioned striatum of a 6-hydroxydopamine lesioned rats, rotational behavior of the rat decreased as much as 80% initially, then slowly returned to baseline over the next four weeks, parallelling graft rejection. Thus, the SVG-TH cells can induce a functional recovery in an animal model of Parkinson's disease, however as a xenograft, the SVG cells are recognized by the immune system.
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PMID:Expression of tyrosine hydroxylase in an immortalized human fetal astrocyte cell line; in vitro characterization and engraftment into the rodent striatum. 868 28

Grafts of embryonic ventral mesencephalic tissue placed in the striatum of 6-hydroxydopamine-lesioned rats survive, and make and receive connections to and from the host brain. The dopaminergic neurons of the graft can grow processes into the host brain, and thereby alleviate many of the behavioral deficits of this form of experimental Parkinson's disease. However, when examined some weeks after implantation, grafted substantia nigra only contains about 5% of the expected complement of dopaminergic neurons. We have examined the time course of loss of grafted neurons. We find that the majority die during the first 7 days after transplantation. However, we have shown previously that three-dimensional cultures with the same dimensions as a graft, made of identical cell suspensions, have much better dopaminergic neuronal survival. There must, therefore, be features in the environment surrounding a graft that are toxic to dopaminergic neurons. A limiting factor in the efficacy of dopaminergic grafts is the small distance over which the neurons are able to grow neurites and form connections in the host brain. We find that the growth of neurites from dopaminergic neurons into the host striatum occurs in two phases. Neurites reach their maximum length within 7 days of transplantation, and this is followed by a much slower process of branch and terminal formation. Since axon growth in the adult brain may be inhibited by a number of factors associated with reactive gliosis, we have immunostained various ages of graft for vimentin, tenascin, chondroitin sulfate proteoglycan (CS-PG) using the CS56 antibody, the DSD-1 proteoglycan, and microglia using the OX-42 antibody. We have compared this staining with that surrounding a simple stab wound. Vimentin staining was initially seen in the graft and in astrocytes immediately surrounding it. By 7 weeks staining was restricted to a ring of astrocytes surrounding the graft. Tenascin, DSD-1, and CS-PG were initially seen in and around the grafts. By 7 weeks they had disappeared from grafts, but CS-PG and tenascin persisted in small amounts around stab wounds. In general, immunostaining of these molecules persisted longer around a stab lesion than around a graft. There was also an intense local microglial reaction surrounding both grafts and stab wounds which had largely resolved by 7 weeks.
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PMID:The time course of loss of dopaminergic neurons and the gliotic reaction surrounding grafts of embryonic mesencephalon to the striatum. 879 70

Rat embryonic d 14 (E14) mesencephalic cells, 2.5% of which are glioblasts, were incubated in medium containing 10% of fetal bovine serum for 12 h and subsequently expanded in a serum-free medium using basic fibroblast growth factor (bFGF) as the mitogen. On a single occasion, after more than 15 d in culture, several islets of proliferating, glial-like cells were observed in one dish. The cells, when isolated and passaged, proliferated rapidly in either a serum-free or serum-containing growth medium. Subsequent immunocytochemical analysis showed that they stained positive for GFAP and vimentin, and negative for A2B5, O4, GalC, and MAP2. Serum-free conditioned medium (CM) prepared from these cells caused a fivefold increase in survival and promoted neuritic expansion of E14 mesencephalic dopaminergic neurons in culture. These actions are similar to those exerted by CM derived from primary, mesencephalic type-1 astrocytes. The pattern of expression of the region-selective genes; wnt-1, en-1, sis showed that 70% of the cells were heteroploid, and of these, 50% were tetraploid. No apparent decline in proliferative capacity has been observed after 25 passages. The properties of this cell line, named ventral mesencephalic cell line one (VMCL1), are consistent with those of an immortalized, type-1 astrocyte. The mesencephalic origin of the cell line, and the pattern and potency of the neurotrophic activity exerted by the CM, strongly suggest that the neurotrophic factor(s) identified are novel, and will likely be strong candidates with clinical utility for the treatment of Parkinson's disease.
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PMID:An immortalized, type-1 astrocyte of mesencephalic origin source of a dopaminergic neurotrophic factor. 1034 91

Mitochondrial dysfunction has been associated with Parkinson's disease. However, the role of mitochondrial defects in the formation of Lewy bodies, a pathological hallmark of Parkinson's disease has not been addressed directly. In this report, we investigated the effects of inhibitors of the mitochondrial electron-transport chain on the aggregation of alpha-synuclein, a major protein component of Lewy bodies. Treatment with rotenone, an inhibitor of complex I, resulted in an increase of detergent-resistant alpha-synuclein aggregates and a reduction in ATP level. Another inhibitor of the electron-transport chain, oligomycin, also showed temporal correlation between the formation of aggregates and ATP reduction. Microscopic analyses showed a progressive evolution of small aggregates of alpha-synuclein to a large perinuclear inclusion body. The inclusions were co-stained with ubiquitin, 20 S proteasome, gamma-tubulin, and vimentin. The perinuclear inclusion bodies, but not the small cytoplasmic aggregates, were thioflavin S-positive, suggesting the amyloid-like conformation. Interestingly, the aggregates disappeared when the cells were replenished with inhibitor-free medium. Disappearance of aggregates coincided with the recovery of mitochondrial metabolism and was partially inhibited by proteasome inhibitors. These results suggest that the formation of alpha-synuclein inclusions could be initiated by an impaired mitochondrial function and be reversed by restoring normal mitochondrial metabolism.
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PMID:Formation and removal of alpha-synuclein aggregates in cells exposed to mitochondrial inhibitors. 1172 69

Association between protein inclusions and neurodegenerative diseases, including Parkinson's and Alzheimer's diseases, and polyglutamine disorders, has been widely documented. Although ubiquitin is conjugated to many of these aggregated proteins, the 26S proteasome does not efficiently degrade them. Mutations in the ubiquitin-protein ligase Parkin are associated with autosomal recessive juvenile Parkinsonism. Although Parkin-positive inclusions are not detected in brains of autosomal recessive juvenile Parkinsonism patients, Parkin is found in Lewy bodies in sporadic disease. This suggests that loss of Parkin ligase activity via mutation, or sequestration to Lewy bodies, is a contributory factor to sporadic disease onset. We now demonstrate that decreased proteasomal activity causes formation of large, noncytotoxic inclusions within the cytoplasm of both neuronal and nonneuronal cells overexpressing Parkin. This is not a general phenomenon as there is an absence of similar inclusions when HHARI, a structural homolog of Parkin, is overexpressed. The inclusions colocalize with ubiquitin and with proteasomes. Furthermore, Parkin inclusions colocalize with gamma-tubulin, acetylated alpha-tubulin, and cause redistribution of vimentin, suggesting aggresome-like properties. Our data imply that lower proteasomal activity, previously observed in brain tissue of Parkinson's disease patients, leads to Parkin accumulation and a concomitant reduction in ligase activity, thereby promoting Lewy body formation.
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PMID:Inhibition of proteasomal activity causes inclusion formation in neuronal and non-neuronal cells overexpressing Parkin. 1293 72

The Parkin gene (PRKN) encodes an E3 protein-ubiquitin ligase for which loss of function is associated with autosomal-recessive juvenile (<20 years) and early-onset Parkinsonism (<45 years). Although detailed pathological reports are scarce, brains from patients with homozygous exonic deletions demonstrate neuronal loss in the substantia nigra, albeit without the Lewy body pathology characteristic of idiopathic Parkinson's disease. However, there are rare descriptions of more florid pathology, including Lewy bodies and tau positive astrocytes in individuals with compound heterozygous mutations. In the present study we examined whether PRKN point mutations, leading to amino acid substitutions, may alter the cellular distribution of the protein produced. Wild-type Parkin was homogeneously distributed throughout the cytoplasm with a small amount of protein in the nucleus after transfection into human embryonic kidney cells. Mutant isoforms with A82E, G328E and C431F amino acid substitutions were also normally distributed. However, two mutant isoforms, R256C and R275W, within RING finger 1 of the Parkin protein (238-293 amino acids), produced an unusual distribution of the protein, with large cytoplasmic and nuclear inclusions. We have replicated this observation in primary cultured neurons and demonstrate, by the accumulation/co-localization of cytoskeletal protein vimentin, that the inclusion bodies are aggresomes, a cellular response to misfolded protein.
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PMID:RING finger 1 mutations in Parkin produce altered localization of the protein. 1451 84


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