In the past decades, there have been numerous studies in the gene therapy for Parkinson's disease (PD), especially in delivering genes of enzymes for dopamine (DA) synthesis. Gene therapy in PD appears to be at the brink of the clinical study phase. However, there are many questions that need to be solved before this approach can be contemplated clinically, especially the question about the control of DA production because too much DA could cause toxicity. Until recently, few studies have investigated the relation between DA production and PD improvement and respective expressed human tyrosine hydroxylase (hTH), human GTP-cyclohydrolase 1 (hGCH1), and human aromatic acid decarboxylase (hAADC) in ex vivo gene therapy for PD. Now, we have developed a simple, fast, and reliable method to assay the activities of TH and AADC and have provided the possibility of ex vivo gene therapy for PD by genetically modifying cells with separate hTH, hGCH1, and hAADC genes. Using the method, we found though hTH, hGCH1, and hAADC genes were expressed, respectively, they could fulfil the function of DA synthesis by incubating together in vitro, and more DA was synthesized in vitro when hTH, hGCH1, and hAADC genes were expressed together rather than hTH and hAADC genes expressed or hTH expressed. The result suggests that we could easily control DA production in ex vivo gene therapy before transplantation. By combining this method and microdialysis, we also could further investigate the DA production in vitro and in vivo and then decide the optimal number and ratio of different transduced cells to improve the therapy of PD. Thus, the method has potential use in ex vivo gene therapy of PD.
Interacting selectively and non-covalently with any protein or protein complex (a complex of two or more proteins that may include other nonprotein molecules).
Evidence
1:
Inferred from Physical InteractionIntAct
The AR (androgen receptor) is a ligand-regulated transcription factor, which belongs to the steroid receptor family and plays an essential role in growth and development of the prostate. Transcriptional activity of steroid receptors is modulated by interaction with co-regulator proteins and yeast two-hybrid analysis is commonly used to identify these steroid receptor-interacting proteins. However, a limitation of conventional two-hybrid systems for detecting AR protein partners has been that they only allow for analysis of the ligand- and DNA-binding domains of the receptor, as its NTD (N-terminal domain) possesses intrinsic transactivation activity. To identify AR N-terminus-interacting proteins, its NTD was used in the RTA (repressed transactivator) system, which is specifically designed for transactivator bait proteins and was shown to be suitable for two-hybrid analysis with the AR NTD. DDC (L-dopa decarboxylase) was detected multiple times as a novel AR-interacting protein, which was subsequently confirmed in vitro and in vivo. Furthermore, transient transfection of DDC in prostate cancer cells strongly enhanced ligand-dependent AR transcriptional activity, an effect that was antagonized using high concentrations of the anti-androgen bicalutamide. Glucocorticoid receptor activity was also strongly enhanced with DDC co-transfection, while oestrogen receptor activity was only mildly affected. Together, our data demonstrate that DDC interacts with AR to enhance steroid receptor transactivation, which may have important implications in prostate cancer progression.
Interacting selectively and non-covalently with pyridoxal 5' phosphate, 3-hydroxy-5-(hydroxymethyl)-2-methyl4-pyridine carboxaldehyde 5' phosphate, the biologically active form of vitamin B6.
Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of an alkaloid stimulus. Alkaloids are a large group of nitrogenous substances found in naturally in plants, many of which have extracts that are pharmacologically active.
Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a drug stimulus. A drug is a substance used in the diagnosis, treatment or prevention of a disease.
Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a growth factor stimulus.
The chemical reactions and pathways resulting in the formation of dopamine, a catecholamine neurotransmitter and a metabolic precursor of noradrenaline and adrenaline.
The chemical reactions and pathways involving isoquinoline alkaloids, alkaloid compounds that contain bicyclic N-containing aromatic rings and are derived from a 3,4-dihydroxytyramine (dopamine) precursor that undergoes a Schiff base addition with aldehydes of different origin.
An aging process that has as participant a whole multicellular organism. Multicellular organism aging includes loss of functions such as resistance to disease, homeostasis, and fertility, as well as wear and tear. Multicellular organisms aging includes processes like cellular senescence and organ senescence, but is more inclusive. May precede death (GO:0016265) of an organism and may succeed developmental maturation (GO:0021700).
Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a pyrethroid stimulus. Pyrethroids are a group of growth regulators, analogous to insect juvenile hormones, that interfere with the development of insect larvae and are used in the control of insects that are harmful in the adult stage.
The chemical reactions and pathways resulting in the formation of serotonin (5-hydroxytryptamine), a monoamine neurotransmitter occurring in the peripheral and central nervous systems, also having hormonal properties.
Protein involved in the synthesis of catecholamines, which are amine derivatives of catechol (2-hydroxyphenol). They are synthesized from the amino acid tyrosine (Tyr) in sympathetic-nerve terminals and in the adrenal gland. Catecholamines act as hormones or neuro- transmitters, e.g. adrenaline, noradrenaline and dopamine.
Enzyme that belongs to the lyase family and which catalyzes the spliting of CO(2) from the carboxylic group of amino acids, beta-keto acids and alpha-keto acids.
Enzyme that catalyzes the cleavage of C-C, C-O, C-S, C-N or other bonds by other means than by hydrolysis or oxidation, with two substrates in one reaction direction, and one in the other. In the latter direction, a molecule (of carbon dioxide, water, etc) is eliminated, thus creating a new double bond or a new ring.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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