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)

GDNF is a pleitropic neurotrophic factor which stimulates the dopaminergic phenotype in vitro and in vivo by way of activation of the GDNF/RET receptor complex. The pharmacologic profile of GDNF in two well-characterized animal models of Parkinson's disease suggests that the molecule may be useful in the treatment of neurodegenerative diseases involving dopaminergic dysfunction such as Parkinson's disease. This review summarizes the preclinical development path which was taken to develop GDNF as a novel therapeutic approach to treat Parkinson's disease based on GDNF's ability to regenerate dopamine neurons, including a description of the pharmacologic/biologic activities of GDNF. The overall aim will be to discuss these issues in the context of their potential therapeutic usefulness of GDNF to treat Parkinson's disease.
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PMID:A preclinical development strategy designed to optimize the use of glial cell line-derived neurotrophic factor in the treatment of Parkinson's disease. 961 19

Receptor-mediated gene transfer is an effective strategy among nonviral vector systems. It is, however, crucial to develop various types of monoclonal antibodies satisfying both the binding specificity for cell targeting and the capacity of endocytosis required for gene transfer. In the present study, we generated a novel monoclonal antibody (NBL-1) to RET, a receptor tyrosine kinase expressed in both neuroblastoma cells and cells present in substantia nigra, a responsive locus of Parkinson's disease. NBL-1, when added to the culture medium of the neuroblastoma cells, was incorporated by endocytosis in a wortmannin-sensitive manner. Using a biotinylated NBL-1 complexed with plasmid DNAs based on electrostatic interaction through avidin-conjugated polylysines, exogenous luciferase genes were expressed in neuroblastoma cells at a more than 10-fold higher level. The expression level of the gene based on NBL-1 was comparable to that obtained by a geneporter system, an improved nonviral gene transduction method. Furthermore, the NBL-1-based gene transfer mediated the formation of more than 20-fold higher numbers of drug-resistant colonies. In contrast, RET-negative cells, which included HeLa, HT1080, Caco-2, and Colo205 cells, did not show any increased expression of an exogenous gene by NBL-1. These data suggest that the RET molecules enable selective gene transduction, and that NBL-1 may possibly be applied to gene therapy for neuroblastomas and Parkinson's disease.
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PMID:Improved gene transfer to neuroblastoma cells by a monoclonal antibody targeting RET, a receptor tyrosine kinase. 1081 Dec 28

Exogenous GDNF as well as vectors containing the gene for this trophic factor has been shown to be neuroprotective in animal models of Parkinson's disease. We therefore investigated whether changes in striatal GDNF protein and nigral mRNA levels of its co-receptors GFRalpha1 and RET occur in response to lesions of dopamine (DA) neurons and examined the temporal profile of these changes as they relate to the loss of dopaminergic markers. Rats were lesioned with 6-hydroxydopamine and sacrificed 3 h to 60 days post-infusion. DA tissue levels in the striatum and tyrosine hydroxylase immunoreactivity in the substantia nigra (SN) and ventral tegmental area (VTA) were used to determine the size of the lesions. GDNF protein was measured in the striatum using radioimmunocytochemistry. In situ hybridization was used to determine alterations in the mRNAs of RET and GFRalpha1 in the SN and VTA. We observed no persistent changes in GDNF protein in the striatum in response to 6-hydroxydopamine over the 60-day observation period, suggesting that compensatory changes in this trophic factor do not occur in response to injury. Dramatic decreases in RET and GFRalpha1 were observed in both SN and VTA that were generally correlated with the loss of TH protein and striatal DA content, strongly suggesting that these receptors are located on DA neurons and that the protective effect of GDNF reflects a direct action of the trophic factor on these neurons.
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PMID:Effect of 6-hydroxydopamine on striatal GDNF and nigral GFRalpha1 and RET mRNAs in the adult rat. 1455 46

In the human embryo, from approximately 6 weeks gestational age (GA), dopaminergic (DA) neurons can be found in the ventral mesencephalon (VM). More specifically, the post-mitotic neurons are located in the ventral part of the tegmentum (VT), whereas no mature DA neurons are found in the neighboring dorsal part. We used Affymetrix HG-U133 GeneChip technology to compare genome-wide expression profiles of ventral and dorsal tegmentum from 8 weeks GA human embryos, in order to identify genes involved in specification, differentiation, and survival of mesencephalic DA (mDA) neurons. Known mDA marker genes including ALDH1A1, DAT1, VMAT2, TH, CALB1, NURR1, FOXA1, GIRK2, PITX3, RET, and DRD2 topped the list of 96 genes from HG-U133A with higher expression in VT, validating the experimental set-up. In addition, 28 probes from HG-U133B were identified whereof most are annotated to UniGene clusters with no gene associated or to genes of unknown function. Of these, the fifteen most regulated transcripts, representing changes down to 56% could be verified by quantitative real-time PCR (Q-PCR) on a developmental series of subdissected human embryonic and fetal brain material, resulting in not only a regional but also a temporal expression profile. This revealed a distinct DA-associated profile for in particular a putative transcription factor (FLJ45455) and the uncharacterized transmembrane proteins KIAA1145 and SLC10A4. The data presented here may help to device cell replacement and regenerative therapies for Parkinson's disease (PD).
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PMID:Identification of novel genes regulated in the developing human ventral mesencephalon. 1647 50

Glial cell line-derived neurotrophic factor (GDNF) has shown robust neuroprotective and neuroreparative activities in various animal models of Parkinson's Disease or amyotrophic lateral sclerosis (ALS). The successful use of GDNF as a therapeutic in humans, however, appears to have been hindered by its poor bioavailability to target neurons in the central nervous system (CNS). To improve delivery of exogenous GDNF protein to CNS motor neurons, we employed chemical conjugation techniques to link recombinant human GDNF to the neuronal binding fragment of tetanus toxin (tetanus toxin fragment C, or TTC). The predominant species present in the purified conjugate sample, GDNF:TTC, had a molecular weight of approximately 80 kDa as determined by non-reducing SDS-PAGE. Like GDNF, addition of GDNF:TTC to culture media of neuroblastoma cells expressing GFRalpha-1/c-RET produced a dose-dependent increase in cellular phospho-c-RET levels. Treatment of cultured midbrain dopaminergic neurons with either GDNF or the conjugate similarly promoted both DA neuron survival and neurite outgrowth. However, in contrast to mice treated with GDNF by intramuscular injection, mice receiving GDNF:TTC revealed intense GDNF immunostaining associated with spinal cord motor neurons in fixed tissue sections. That GDNF:TTC provided neuroprotection of axotomized motor neurons in neonatal rats further revealed that the conjugate retained its GDNF activity in vivo. These results indicate that TTC can serve as a non-viral vehicle to substantially improve the delivery of functionally active growth factors to motor neurons in the mammalian CNS.
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PMID:A glial cell line-derived neurotrophic factor (GDNF):tetanus toxin fragment C protein conjugate improves delivery of GDNF to spinal cord motor neurons in mice. 1702 Jul 49

Glial cell-line derived neurotrophic factor (GDNF)-mediated RET tyrosine kinase signaling is implicated in the survival of several PNS and CNS neuronal populations that are important in the pathogenesis of several disorders including Parkinson's disease and drug addiction. However, it has been difficult to study these processes and the physiological importance of this pathway in adult mice because of the neonatal lethality of Gdnf and Ret null mice. We report successful creation of RET conditional reporter mice to investigate postnatal physiologic roles of RET and monitor the fate of RET-expressing cell types. To delete RET specifically in dopaminergic neurons and determine the physiologic requirement of RET in the maintenance of substantia nigra compacta (SNC) and ventral tegmental area (VTA), we bred the RET conditional mice with mice that specifically express Cre from the dopamine transporter (Dat) locus. A detailed morphometric and biochemical analysis including dopaminergic neuron number and size in SNC and VTA, and fiber density in the striatum and nucleus accumbens, and dopamine levels indicate that RET is not required for providing global trophic support to midbrain dopaminergic neurons in adult mice. Furthermore, RET deficiency in these neurons does not cause major sensorimotor abnormalities. Hence our results support the idea that RET signaling is not critical for the normal physiology of the SNC and VTA in adult mice.
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PMID:RET is dispensable for maintenance of midbrain dopaminergic neurons in adult mice. 1706 62

Activation of the RET (rearranged during transfection) receptor by glial cell-line-derived neurotrophic factor (GDNF) has been identified as an important differentiation and survival factor for dopaminergic neurons of the midbrain in preclinical experiments. These encouraging results have led to clinical trials of GDNF in patients with Parkinson's disease, which have resulted in conflicting findings. To investigate the potential benefit of Ret-dependent signaling on the challenged dopaminergic system, we tested the effect of tissue-selective ablation of the Ret gene on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice, the most widely used animal model for Parkinson's disease. Ablation of Ret did not modify the MPTP-induced loss of dopaminergic neurons in the substantia nigra pars compacta and the dopaminergic innervation of the striatum at 14 days. However, Ret ablation abolished the regeneration of dopaminergic fibers and terminals, as well as the partial recovery of striatal dopamine concentrations, that was observed in control mice between days 14 and 90 after MPTP treatment. We therefore conclude that RET signaling has no influence on the survival of dopaminergic neurons in the MPTP model of Parkinson's disease but rather facilitates the regeneration of dopaminergic axon terminals.
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PMID:RET signaling does not modulate MPTP toxicity but is required for regeneration of dopaminergic axon terminals. 1805 10

The aim of the present study is to provide a review of the expression and action of trophic factors in the carotid body. In glomic type I cells, the following factors have been identified: brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, artemin, ciliary neurotrophic factor, insulin-like growth factors-I and -II, basic fibroblast growth factor, epidermal growth factor, transforming growth factor-alpha and -beta1, interleukin-1beta and -6, tumour necrosis factor-alpha, vascular endothelial growth factor, and endothelin-1 (ET-1). Growth factor receptors in the above cells include p75LNGFR, TrkA, TrkB, RET, GDNF family receptors alpha1-3, gp130, IL-6Ralpha, EGFR, FGFR1, IL1-RI, TNF-RI, VEGFR-1 and -2, ETA and ETB receptors, and PDGFR-alpha. Differential local expression of growth factors and corresponding receptors plays a role in pre- and postnatal development of the carotid body. Their local actions contribute toward producing the morphologic and molecular changes associated with chronic hypoxia and/or hypertension, such as cellular hyperplasia, extracellular matrix expansion, changes in channel densities, and neurotransmitter patterns. Neurotrophic factor production is also considered to play a key role in the therapeutic effects of intracerebral carotid body grafts in Parkinson's disease. Future research should also focus on trophic actions on carotid body type I cells by peptide neuromodulators, which are known to be present in the carotid body and to show trophic effects on other cell populations, that is, angiotensin II, adrenomedullin, bombesin, calcitonin, calcitonin gene-related peptide, cholecystokinin, erythropoietin, galanin, opioids, pituitary adenylate cyclase-activating polypeptide, atrial natriuretic peptide, somatostatin, tachykinins, neuropeptide Y, neurotensin, and vasoactive intestinal peptide.
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PMID:Trophic factors in the carotid body. 1877 56

Rearranged during transfection, RET, is a receptor tyrosine kinase expressed in neural crest derived cell lineages. RET is activated by dimerisation facilitated by its binding to the heterodimeric complex formed by Glial cell-derived neurotrophic factor (GDNF) -family ligand (GFL) and GNDF-family receptor (GFR). Both GDNFs and their co-receptors are a small protein family of four members. RET kinase mediated signaling can lead to survival, cell growth, differentiation, and migration. Pharmaceutically RET is of interest due to its involvement in several disease conditions. Oncogenic RET activation by mutations or rearragements predisposes to cancers like multiple endocrine neoplasia type 2 (A and B) and medullary thyroid carcinoma. Loss-of-function mutations in RET are a strong susceptibility factor for Hirschsprung disease, which is characterized by lack of ganglion cells in gastrointestinal tract. All the GFLs promote neuronal survival and GDNF is one of the most potent neurotrophic factors for dopaminergic neurons. Therefore, the neuroprotective capacity of RET activation to override the apoptotic program in neurodegenerative diseases, like in dying midbrain dopaminergic neurons in Parkinson's disease, is of great interest. This article reviews the recent international patents on modulation of RET kinase activity by small-molecule and peptide-based agonists and antagonists.
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PMID:Recent inventions on receptor tyrosine kinase RET modulation. 1907 52

Neurotrophic factors promote survival, proliferation and differentiation of neurons inducing intracellular signaling via specific receptors. The conventional biochemical methods often fail to reveal full repertoire of neurotrophic factor-receptor interactions because of their limited sensitivity. We evaluated several approaches to study signaling of Glial cell line-Derived Neurotrophic Factor (GDNF) family ligands and found that reporter-gene systems possess exceptionally high sensitivity and a heuristic power to identify novel biologically relevant growth factor-receptor interactions. We identified persephin, a GDNF family member, as a novel ligand for GFRalpha1/RET receptor complex. We confirmed this finding by several independent methods, including neurite outgrowth assay from the explants of sympathetic ganglia expressing Gfralpha1 and Ret mRNA but not persephin's conventional receptor GFRalpha4. As the activation of GFRalpha1/RET was shown to rescue dopaminergic neurons, our results suggest the potential of persephin for the treatment of Parkinson's disease.
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PMID:Persephin signaling through GFRalpha1: the potential for the treatment of Parkinson's disease. 2035 May 99


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