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)

Loss-of-function mutations in the parkin gene were first identified in autosomal recessive juvenile parkinsonism (AR-JP). Subsequently, parkin mutations were found in many early-onset patients with Parkinson's disease (PD) (<45 years at onset). We hypothesized that parkin gene expression also may contribute to the age-associated risk of idiopathic PD (>50 years at onset). Two single-nucleotide polymorphisms within the parkin core promoter have been identified and assessed. We show one of the variants, -258 T/G, is located in a region of DNA that binds nuclear protein from human substantia nigra in vitro and functionally affects gene transcription. Furthermore, the -258 T/G polymorphism is genetically associated with idiopathic PD, as assessed in a large population-based series of cases and controls. Our results further implicate the parkin gene in the development of Parkinson's disease.
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PMID:Functional association of the parkin gene promoter with idiopathic Parkinson's disease. 1237 68

The putative dopaminergic (DA) neurons intrinsic to the human striatum were studied by applying immunofluorescence and quantitative methods to postmortem tissue from seven normal individuals. Stringent morphological and chemical criteria were used to identify striatal DA neurons, including immunostaining for tyrosine hydroxylase, DA transporter and neuronal nuclear protein. The DA neurons were scattered throughout the striatum, but abounded particularly in its ventral portion. Frequency distribution of surface areas of DA cell bodies reveals that the most frequent DA neurons (x =58.0%, S.D.=12.8%) had a medium-sized (approximately 200+/-15 microm2) perikaryon with 3-5 varicose dendrites, whereas others (x =35.5%, S.D.=14.0%) had a smaller (approximately 140+/-15 microm2) perikaryon with 3-4 varicose dendrites. There was a small number (x =6.5%, S.D.=8.5%) of larger DA neurons (209-584 microm2) with spiny dendrites and a few TH-immunoreactive cells displaying mixed neuron-glia morphology. Despite significant inter-individual variations in neuron density, the human striatum (mean volume of 8.76 cm3) harbored a mean of 331.9 DA neurons (S.D.=199.2). A prolific zone, containing about 3000 cells, occurred in the ventral striatum in two brains. The addition of these cells would increase by about 10 times the total number of striatal DA neurons, which should not be confounded with segments of nigrostriatal DA fibers that displayed large (8-12 microm) varicosities and looked like small bipolar neurons. The function of striatal DA neurons is unknown but the fact that their number increases markedly following lesion of nigral DA input or administration of various growth factors, opens up new therapeutic avenues for treatment of Parkinson's disease.
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PMID:Morphology and distribution of dopaminergic neurons intrinsic to the human striatum. 1558 97

Alpha-synuclein containing cellular inclusions are a hallmark of Parkinson Disease, Lewy Body Dementia, and Multiple System Atrophy. A genome wide expression screen was performed in C. elegans overexpressing both wild-type and A53T human alpha-synuclein. 433 genes were up- and 67 genes down-regulated by statistical and fold change (> or <2) criteria. Gene ontology (GO) categories within the regulated gene lists indicated over-representation of development and reproduction, mitochondria, catalytic activity, and histone groups. Seven genes (pdr-1, ubc-7, pas-5, pas-7, pbs-4, RPT2, PSMD9) with function in the ubiquitin-proteasome system and 35 mitochondrial function genes were up-regulated. Nine genes that form histones H1, H2B, and H4 were down-regulated. These results demonstrate the effects of alpha-synuclein on proteasome and mitochondrial complex gene expression and provide further support for the role of these complexes in mediating neurotoxicity. The results also indicate an effect on nuclear protein genes that suggests a potential new avenue for investigation.
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PMID:Identification of gene expression changes in transgenic C. elegans overexpressing human alpha-synuclein. 1662 60

While isolating morphine-dependence-related genes with differential display, we cloned a novel human gene, zinc finger CCHC-type and RNA-binding motif 1 (ZCRB1, alias MADP-1) encoding a nuclear protein (217 residues). The ZCRB1 gene consists of eight exons and seven introns. It is mapped to 12q12, which is within a locus reported for Parkinson disease (M. Funayama et al., Ann. Neurol. 51 (2002) 296-301). The 5'-flanking region contains an enhancer core motif and binding sites for AP-1, AP-2, and LF-A1. ZCRB1 is characterized by an RNA-binding motif and a CCHC zinc finger motif. The latter overlaps the C..C...GH....C core nucleocapsid motif. ZCRB1 is conserved from zebrafish to human and shares homology with cold-inducible RNA-binding protein. Transfection assay showed that ZCRB1 is located in the nucleoplasm, but outside the nucleolus. ZCRB1 gene expression was stimulated by morphine, inhibited by 30-36 degrees C, and up-regulated by 39 degrees C incubation in SH-SY5Y neural cells. Zcrb1 gene expression is highest in the heart and testes, lower in the cerebellum, and lowest in the liver in mice. ZCRB1 mRNA expression is specifically elevated in hepatocarcinoma HepG2 cells. These data provide new clues for further understanding of morphine dependence, heat shock, and hepatocarcinoma.
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PMID:Isolation, expression, and characterization of the human ZCRB1 gene mapped to 12q12. 1695 69

Reactive oxygen species (ROS) play an important role in the pathogenesis of airway inflammation and hyperresponsiveness. Recent studies have demonstrated that antioxidants are able to reduce airway inflammation and hyperreactivity in animal models of allergic airway disease. A newly developed antioxidant, small molecular weight thiol compound, N-acetylcysteine amide (AD4) has been shown to increase cellular levels of glutathione and to attenuate oxidative stress related disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. However, the effects of AD4 on allergic airway disease such as asthma are unknown. We used ovalbumin (OVA)-inhaled mice to evaluate the role of AD4 in allergic airway disease. In this study with OVA-inhaled mice, the increased ROS generation, the increased levels of Th2 cytokines and VEGF, the increased vascular permeability, the increased mucus production, and the increased airway resistance in the lungs were significantly reduced by the administration of AD4. We also found that the administration of AD4 decreased the increases of the NF-kappaB and hypoxia-inducible factor-1alpha (HIF-1alpha) levels in nuclear protein extracts of lung tissues after OVA inhalation. These results suggest that AD4 attenuates airway inflammation and hyperresponsiveness by regulating activation of NF-kappaB and HIF-1alpha as well as reducing ROS generation in allergic airway disease.
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PMID:A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-kappaB and hypoxia-inducible factor-1alpha. 1816 Aug 46

Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear protein best known to facilitate DNA base excision repair. Recent work has expanded the physiologic functions of PARP-1, and it is clear that the full range of biologic actions of this important protein are not yet fully understood. Regulation of the product of PARP-1, poly(ADP-ribose) (PAR), is a dynamic process with PAR glycohydrolase playing the major role in the degradation of the polymer. Under pathophysiologic situations overactivation of PARP-1 results in unregulated PAR synthesis and widespread neuronal cell death. Once thought to be necrotic cell death resulting from energy failure, we have found that PARP-1-dependent cell death is dependent on the generation of PAR, which triggers the nuclear translocation of apoptosis-inducing factor resulting in caspase-independent cell death. This form of cell death is distinct from apoptosis, necrosis, or autophagy and is termed parthanatos. PARP-1-dependent cell death has been implicated in tissues throughout the body and in diseases afflicting hundreds of millions worldwide, including stroke, Parkinson's disease, heart attack, diabetes, and ischemia reperfusion injury in numerous tissues. The breadth of indications for PARP-1 injury make parthanatos a clinically important form of cell death to understand and control.
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PMID:Mitochondrial and nuclear cross talk in cell death: parthanatos. 1907 45

Mesenchymal stem cells (MSCs) constitute an interesting cellular source to promote brain regeneration after Parkinson's disease. MSCs have significant advantages over other stem cell types, and greater potential for immediate clinical application. The aim of this study was to investigate whether MSCs from the human placenta could be induced to differentiate into dopaminergic cells. MSCs from the human placenta were isolated by digestion and density gradient fractionation, and their cell surface glycoproteins were analyzed by flow cytometry. These MSCs were cultured under conditions promoting differetiation into adipocytes and osteoblasts. Using a cocktail that includes basic fibroblast growth factor (bFGF), all trans retinoic acid (RA), ascorbic acid (AA) and 3-isobutyl-1-methylxanthine (IBMX), the MSCs were induced in vitro to become dopamine (DA) neurons. Then, the expression of the mRNA for the Nestin and tyrosine hydroxylase (TH) genes was assayed via RT-PCR. The expression of the Nestin, dopamine transporter (DAT), neuronal nuclear protein (NeuN) and TH proteins was determined via immunofluorescence. The synthesized and secreted DA was determined via ELISA. We found that MSCs from the human placenta exhibited a fibroblastoid morphology. Flow cytometric analyses showed that the MSCs were positive for CD44 and CD29, and negative for CD34, CD45, CD106 and HLA-DR. Moreover, they could be induced into adipocytes and osteocytes. When the MSCs were induced with bFGF, RA, AA and IBMX, they showed a change in morphology to that of neuronal-like cells. The induced cells expressed Nestin and TH mRNA, and the Nestin, DAT, NeuN and TH proteins, and synthesized and secreted DA. Our results suggest that MSCs from the human placenta have the ability to differentiate into dopaminergic cells.
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PMID:The differentiation of human placenta-derived mesenchymal stem cells into dopaminergic cells in vitro. 1941 74

TDP-43 is a nuclear protein involved in exon skipping and alternative splicing. Recently, TDP-43 has been identified as the pathological signature protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis. In addition, TDP-43-positive inclusions are present in Parkinson disease, dementia with Lewy bodies, and 30% of Alzheimer disease cases. Pathological TDP-43 is redistributed from the nucleus to the cytoplasm, where it accumulates. An approximately 25-kDa C-terminal fragment of TDP-43 accumulates in affected brain regions, suggesting that it may be involved in the disease pathogenesis. Here, we show that overexpression of the 25-kDa C-terminal fragment is sufficient to cause the mislocalization and cytoplasmic accumulation of endogenous full-length TDP-43 in two different cell lines, thus recapitulating a key biochemical characteristic of TDP-43 proteinopathies. We also found that TDP-43 mislocalization is associated with a reduction in the low molecular mass neurofilament mRNA levels. Notably, we show that the autophagic system plays a role in TDP-43 metabolism. Specifically, we found that autophagy inhibition increases the accumulation of the C-terminal fragments of TDP-43, whereas inhibition of mTOR, a key protein kinase involved in autophagy regulation, reduces the 25-kDa C-terminal fragment accumulation and restores TDP-43 localization. Our results suggest that autophagy induction may be a valid therapeutic target for TDP-43 proteinopathies.
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PMID:Rapamycin rescues TDP-43 mislocalization and the associated low molecular mass neurofilament instability. 1965 85

Quantification of neuronal cell number is a key endpoint in the characterization of neurodegenerative disease models and neuroprotective regimens. Immunohistochemistry for phenotypic markers, followed by unbiased stereology is often used to quantify the relevant neuronal population. To control for loss of phenotypic markers in the absence of cell death, or to determine if other types of neurons are lost, a general neuronal marker is often desired. Vertebrate neuron-specific nuclear protein (NeuN) is reportedly expressed in most mammalian neurons. In Parkinson's disease models, NeuN has been widely used to determine if there is actual nigral dopamine neuron loss or simply loss of tyrosine hydroxylase expression, a prominent phenotypic marker. To date, the qualitative value of NeuN expression as such a marker in the substantia nigra has not been assessed. Midbrain tissue sections from control rats were stained for NeuN and tyrosine hydroxylase and assessed by light or confocal microscopy. Here we report that NeuN expression level in the rat substantia nigra was highly variable, with many faintly stained cells that would not be meet stereological scoring criteria. Additionally, dopamine neurons with little or no NeuN expression were readily identified. Subcellular compartmentalization of NeuN expression was also variable, with many cells dorsal and ventral to the nigra exhibiting expression in both the nucleus and cytoplasm. NeuN expression also appeared to be much higher in non-dopamine neurons within the ventral midbrain. This characterization of nigral NeuN expression suggests that it is not useful as a quantitative general neuronal marker in the substantia nigra.
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PMID:NeuN is not a reliable marker of dopamine neurons in rat substantia nigra. 1968 46

We examined the transduction efficiency of different adeno-associated virus (AAV) capsid serotypes encoding for green fluorescent protein (GFP) flanked by AAV2 inverted terminal repeats in the nonhuman primate basal ganglia as a prelude to translational studies, as well as clinical trials in patients with Parkinson's disease (PD). Six intact young adult cynomolgus monkeys received a single 10 microl injection of AAV2/1-GFP, AAV2/5-GFP, or AAV2/8-GFP pseudotyped vectors into the caudate nucleus and putamen bilaterally in a pattern that resulted in each capsid serotype being injected into at least four striatal sites. GFP immunohistochemistry revealed excellent transduction rates for each AAV pseudotype. Stereological estimates of GFP+ cells within the striatum revealed that AAV2/5-GFP transduces significantly higher number of cells than AAV2/8-GFP (P < 0.05) and there was no significant difference between AAV2/5-GFP and AAV2/1-GFP (P = 0.348). Consistent with this result, Cavalieri estimates revealed that AAV2/5-GFP resulted in a significantly larger transduction volume than AAV2/8-GFP (P < 0.05). Each pseudotype transduced striatal neurons effectively [>95% GFP+ cells colocalized neuron-specific nuclear protein (NeuN)]. The current data suggest that AAV2/5 and AAV2/1 are superior to AAV2/8 for gene delivery to the nonhuman primate striatum and therefore better candidates for therapeutic applications targeting this structure.
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PMID:Differential transduction following basal ganglia administration of distinct pseudotyped AAV capsid serotypes in nonhuman primates. 1977 46


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