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 DNA fragment of about 13 kb containing the human tyrosine hydroxylase (TH) promoter was previously isolated from a genomic DNA library and sequenced. The 11 kb from the transcription start of the human TH promoter was successively joined to the green fluorescent protein (GFP) to generate a transgenic mouse model. High levels of GFP expression could be observed in TH-positive cells of the Substantia nigra of embryonic and adult mice. Intriguingly, the sequence of the human TH promoter showed a low degree of homology with the mouse and rat TH promoters. In fact, comparative analysis of the sequences of human, rat, and mouse TH promoters revealed only five small regions of high homology. These five evolutionarily conserved regions were numbered in numeric progression from the 5' end of human TH promoter. In the present study, a panel of minimal human TH promoters was generated to analyze the transcriptional activity and specificity of gene expression conferred by the five conserved regions (CRs). The series of constructs was termed 250 bp and contained the first -194 bp of the human TH promoter immediately upstream of the transcription start, the first 35 bp the human TH messenger RNA leader, plus one or more of the five CRs. All the constructs were assembled in a self-inactivating form of the latest series of lentiviral vector system based on the human immunodeficiency virus type 1 (HIV-1). Lentiviral-mediated gene transfer was highly efficient for the in vitro transduction of human neuronal progenitor cells (hNPCs). Since a subset of hNPCs express TH following in vitro treatment with a mixture of differentiating agents, it was possible to assess specificity of expression for all the minimal human TH promoters. Overall, the successive addition of the five conserved regions produced a greater degree of specificity in induced TH-positive hNPCs, in particular after the addition of CRI (-8,917, -8,876). However, the human TH minimal promoters did not show any specificity for TH-positive differentiated mouse primary striatal and S. nigra cells, indicating a difference of TH gene regulation between the human and mouse systems. The human TH minimal promoters may provide the opportunity for the selection of TH-positive human embryonic and adult stem cells for brain transplantation experiments in animal models for Parkinson's disease.
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PMID:Characterization of five evolutionary conserved regions of the human tyrosine hydroxylase (TH) promoter: implications for the engineering of a human TH minimal promoter assembled in a self-inactivating lentiviral vector system. 1574 73

We previously reported a linkage region on chromosome 1p (LOD = 3.41) for genes controlling age at onset (AAO) in Parkinson disease (PD). This region overlaps with the previously reported PARK10 locus. To identify the gene(s) associated with AAO and risk of PD in this region, we first applied a genomic convergence approach that combined gene expression and linkage data. No significant results were found. Second, we performed association mapping across a 19.2-Mb region centered under the AAO linkage peak. An iterative association mapping approach was done by initially genotyping single-nucleotide polymorphisms at an average distance of 100 kb apart and then by increasing the density of markers as needed. Using the overall data set of 267 multiplex families, we identified six associated genes in the region, but further screening of a subset of 83 families linked to the chromosome 1 locus identified only two genes significantly associated with AAO in PD: the gamma subunit of the translation initiation factor EIF2B gene (EIF2B3), which was more significant in the linked subset and the ubiquitin-specific protease 24 gene (USP24). Unexpectedly, the human immunodeficiency virus enhancer-binding protein 3 gene (HIVEP3) was found to be associated with risk for susceptibility to PD. We used several criteria to define significant results in the presence of multiple testing, including criteria derived from a novel cluster approach. The known or putative functions of these genes fit well with the current suspected pathogenic mechanisms of PD and thus show great potential as candidates for the PARK10 locus.
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PMID:Identification of risk and age-at-onset genes on chromosome 1p in Parkinson disease. 1598 17

In susceptible strains of mice, infection with the mutant retrovirus MoMuLV-ts1 causes a neurodegeneration and immunodeficiency syndrome that resembles human human immunodeficiency virus-acquired immunodeficiency syndrome (HIV-AIDS). In this study the authors show increased expression of cyclooxygenase-2 (COX-2) in the brainstem tissues of ts1-infected mice. Up-regulated central nervous system (CNS) levels of this enzyme are associated with HIV-associated dementia and other inflammatory and neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. In brainstem sections, the authors find that astrocytes surrounding spongiform lesions contain increased amounts of immunoreactive COX-2. COX-2 is also up-regulated in cultured ts1-infected cells from the C1 astrocytic cell line, and activation of c-Jun N-terminal kinase, or JNK, pathway. Markers of endoplasmic reticulum (ER) stress, specifically the CCAAT/enhancer-binding protein (CHOP), the glucose-related protein 78 (GRP78), and phosphorylated eukaryotic initiation factor 2 alpha (eIF2 alpha), were also up-regulated in ts1-infected C1 astrocytes. Up-regulation of COX-2 and the above ER signaling factors was reversed by treatment of the infected cells with curcumin which specifically inhibits the JNK/c-Jun pathway. These findings indicate that the JNK/c-Jun pathway is most likely responsible for COX-2 expression induced by ts1 in astrocytes, and that ts1 infection in astrocytes may lead to up-regulation of both inflammatory and ER stress pathways in the central nervous system. Because COX-2 inhibitors are now widely used to treat inflammatory conditions in animals and humans, this finding suggests that these drugs may be useful for therapeutic intervention in neurodegenerative syndromes as well.
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PMID:Up-regulation of astrocyte cyclooxygenase-2, CCAAT/enhancer-binding protein-homology protein, glucose-related protein 78, eukaryotic initiation factor 2 alpha, and c-Jun N-terminal kinase by a neurovirulent murine retrovirus. 1603 95

Brain mononuclear phagocytes (MP, bone marrow monocyte-derived macrophages, perivascular macrophages, and microglia) function to protect the nervous system by acting as debris scavengers, killers of microbial pathogens, and regulators of immune responses. MP are activated by a variety of environmental cues and such inflammatory responses elicit cell injury and death in the nervous system. MP immunoregulatory responses include secretion of neurotoxic factors, mobilization of adaptive immunity, and cell chemotaxis. This incites tissue remodelling and blood-brain barrier dysfunction. As disease progresses, MP secretions engage neighboring cells in a vicious cycle of autocrine and paracrine amplification of inflammation leading to tissue injury and ultimately destruction. Such pathogenic processes tilt the balance between the relative production of neurotrophic and neurotoxic factors and to disease progression. The ultimate effects that brain MP play in disease revolves "principally" around their roles in neurodegeneration. Importantly, common functions of brain MP in neuroimmunity link highly divergent diseases (for example, human immunodeficiency virus type-one associated dementia, Alzheimer's disease and Parkinson's disease). Research into this process from our own laboratories and those of others seek to harness MP inflammatory processes with the intent of developing therapeutic interventions that block neurodegenerative processes and improve the quality of life in affected people.
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PMID:Mononuclear phagocytes in the pathogenesis of neurodegenerative diseases. 1626 Mar 84

The differential characteristics of lentiviral vectors based on human and simian immunodeficiency viruses (HIV and SIV) were investigated in rats and monkeys. Each vector was injected into the striatum, and the expression patterns of the marker gene green fluorescent protein (GFP) were analyzed in the basal ganglia. With respect to the capability of gene delivery to neural cells, the HIV-based vector exhibited a higher tropism to neurons than to astroglias in the striatum, and vice versa for the SIV-based vector. The preferential direction of axonal transport of striatally expressed GFP was also examined in the present study. The HIV-based vector allowed for both anterograde transport via the striatopallidal and striatonigral pathways and retrograde transport via the nigrostriatal pathway. The GFP labeling of axon terminals through anterograde transport was apparent regardless of the animal species, while that of neuronal cell bodies through retrograde transport was much more prominent in monkeys than in rats. As for the SIV-based vector, on the other hand, evidence for anterograde transport was obtained much more markedly in monkeys than in rats, and only weak or no retrograde transport occurred in either monkeys or rats. Our results indicate that HIV-based, but not SIV-based, lentiviral vectors possess the high tropism to neurons and permit retrograde transport of an expressed gene, especially in primates. The latter property might carry a potential benefit in gene therapy for Parkinson's disease, as stereotaxic injections of the vectors could be performed into the striatum, spatially larger than the substantia nigra, with greater certainty.
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PMID:Differential characteristics of HIV-based versus SIV-based lentiviral vector systems: Gene delivery to neurons and axonal transport of expressed gene. 1727 14

Protease-activated receptors (PARs) are G protein-coupled receptors that regulate the cellular response to extracellular serine proteases, like thrombin, trypsin, and tryptase. The PAR family consists of four members: PAR-1, -3, and -4 as thrombin receptors and PAR-2 as the trypsin/tryptase receptor, which are abundantly expressed in the brain throughout development. Recent evidence has supported the direct involvement of PARs in brain development and function. The expression of PARs in the brain is differentially upregulated or downregulated under pathological conditions in neurodegenerative disorders, like Parkinson's disease, Alzheimer's disease, multiple sclerosis, stroke, and human immunodeficiency virus-associated dementia. Activation of PARs mediates cell death or cell survival in the brain, depending on the amplitude and the duration of agonist stimulation. Interference or potentiation of PAR activation is beneficial in animal models of neurodegenerative diseases. Therefore, PARs mediate either neurodegeneration or neuroprotection in neurodegenerative diseases and represent attractive therapeutic targets for treatment of brain injuries. Here, we review the abnormal expression of PARs in the brain under pathological conditions, the functions of PARs in neurodegenerative disorders, and the molecular mechanisms involved.
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PMID:Protease-activated receptors in the brain: receptor expression, activation, and functions in neurodegeneration and neuroprotection. 1791 33

Chemokines and chemokine receptors, primarily found to play a role in leukocyte migration to the inflammatory sites or to second lymphoid organs, have recently been found expressed on the resident cells of the central nervous system (CNS). These proteins are important for the development of the CNS and are involved in normal brain functions such as synaptic transmission. Increasing lines of evidence have implicated an involvement for chemokines and their receptors in several neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), human immunodeficiency virus-associated dementia (HAD), multiple sclerosis (MS), and stroke. Specific inhibition of the biological activities of chemokine receptors could gain therapeutic benefit for these neurodegenerative disorders. In recent years, non-peptide antagonists of chemokine receptors have been disclosed and tested in relevant pharmacological models and some of these inhibitors have entered clinical trials. The aim of this review is to outline the recent progress regarding the role of chemokines and their receptors in neurodegenerative diseases and the advancements in the development of chemokine receptor inhibitors as potential therapeutic approaches for these neurodegenerative diseases.
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PMID:The many roles of chemokine receptors in neurodegenerative disorders: emerging new therapeutical strategies. 1797 99

Neural stem cells (NSCs) have the potential to be used for the treatment of Parkinson's disease (PD), as they can be expanded, manipulated and differentiated in vitro to generate dopaminergic neurones which are suitable for transplantation. Since NSCs have a tendency to follow an astrocytic lineage after differentiation in vitro, researchers are investigating ways to induce a neuronal phenotype in these cells. In this study, the human immunodeficiency virus 1 (HIV-1) transactivator of transcription (TAT) protein transduction domain (PTD) system was used in an attempt to promote neuronal differentiation in rodent NSCs. A fusion protein that incorporated both the TAT PTD and the Pax6 protein (a determinant of neurogenesis) was created and added to the differentiation phase of embryonic day (E) 12 rat ventral mesencephalic (VM) neurosphere cultures. Subsequently, application of dopaminergic growth factors (GFs) was used in an attempt to induce the newly-generated neuronal progenitors to adopt a dopaminergic phenotype. In addition, a technique involving the differentiation of intact neurospheres (instead of the differentiation of neurosphere-derived dissociated cells) was investigated for its ability to promote dopaminergic neurogenesis. Immunocytochemical analysis of the differentiated neurosphere cultures indicated that both of these techniques had a significant effect on the emergence of dopaminergic neurones. Moreover, upon combination of these techniques, a further increase in dopaminergic neuronal generation was observed. Based on the findings of the present study, it is clear that NSCs are greatly influenced by their environment and that optimised in vitro conditions can support the potential of these cells to differentiate into dopaminergic neurones.
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PMID:TAT-PAX6 protein transduction in neural progenitor cells: a novel approach for generation of dopaminergic neurones in vitro. 1838 97

In this era of genomics and other exciting technical advances, research on the biology of aging is undergoing a renaissance. This report summarizes 10 cutting-edge areas of research covered in symposia that spanned such topics as stem cells, novel vaccine strategies, nutritional sensing, new concepts of Parkinson's disease, high throughput screening for aging interventions, manipulating telomerase in cancer and immunodeficiency, synergy between aging and HIV disease, and epigenetic influences on aging. Novel animal models, including those showing no evidence of aging, as well as ethical and political implications of embryonic stem cells and alternative medicine are also discussed.
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PMID:The biological sciences section program at the 60th Annual Meeting of the Gerontological Society of America. 1842 56

Leucine-rich alpha-2-glycoprotein-1 (LRG) is a serum glycoprotein of unknown function that has shown promise based on qualitative assessments as a biomarker for certain diseases including microbial infections and cancer. However, the lack of a quantitative assay for LRG has limited its application. Here an indirect enzyme-linked immunosorbent assay (ELISA) for quantifying LRG in human serum is described in which cytochrome c is employed as the capturing ligand and a monoclonal antibody specific for LRG is used to detect the captured glycoprotein. Application of this assay in quantifying LRG in various patients' sera is demonstrated. The concentration of LRG in sera of control subjects as determined by this assay is approximately 50 microg/ml. Consistent with expectations from published reports, LRG was found to be significantly elevated in the sera of some patients with a bacterial infection (toxic shock syndrome, TSS). LRG was only slightly elevated in patients infected with the human immunodeficiency virus as compared to uninfected control subjects, while normal levels of LRG were observed in patients with non-infectious diseases (inflammatory arthritis and neurological disorders, primarily Parkinson's disease). Although LRG and C-reactive protein (CRP) are both produced by the liver and are classified as acute-phase proteins, there was no significant correlation between the levels of LRG and CRP in the sera of the patients. Thus, LRG and CRP measurements are non-redundant and indicate different physiological contexts. The ELISA described in this report should be useful to further assess serum LRG as a biomarker for clinical diagnostics.
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PMID:ELISA for human serum leucine-rich alpha-2-glycoprotein-1 employing cytochrome c as the capturing ligand. 1843 31


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