Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leucine-rich repeat-containing G-protein-coupled receptor 8 (LGR8; also classified as relaxin family peptide 2 receptor; RXFP2) has been identified as a cognate receptor for the peptide hormone, insulin-like peptide 3 (INSL3) and INSL3-LGR8 signaling plays an essential role in testis descent and germ cell development in human and rodents. Lgr8 mRNA has been detected in human tissues including testis, kidney and brain, but its regional and cellular distribution in these tissues in human or other species is largely unknown. In an initial step to elucidate the physiological function of a putative INSL3-LGR8 system in rat brain, the localization of Lgr8 mRNA was investigated using in situ hybridization histochemistry, revealing a discrete distribution in forebrain, with expression highly enriched in the thalamus. High densities were detected in the parafascicular nucleus (Pf), the dorsolateral, ventrolateral and posterior thalamic nuclei, and in the medial habenula. Lgr8 transcripts were also detected in frontal and motor cortices. The comparative distribution of LGR8 (receptor protein) was examined by autoradiography of [125I]-human INSL3 binding sites, with high densities detected in the thalamus, especially in Pf, and in the entire striatum--the caudate putamen (CPmicro), islands of Calleja, olfactory tubercle, nucleus accumbens--with lower levels in distinct layers of cerebral cortex. Notably, these areas also receive dopaminergic projections. These findings demonstrate the existence of LGR8 in neuronal soma in the thalamus and axons/terminals in thalamic target areas such as the striatum and frontal cortex. LGR8 was also detected throughout the medial habenula-fasciculus retroflexus-interpeduncular nucleus pathway, further indicating that the receptor is transported from mRNA-expressing soma to remote axonal/terminal sites. These findings suggest the existence of a broadly distributed LGR8 signaling system in the rat involved in sensorimotor, limbic and cognitive functions. Further studies are now required to elucidate the precise function of LGR8, under normal and pathological conditions, as importantly, several of the equivalent receptor-positive areas in human brain are part of the pathology of neurodegenerative conditions including Parkinson's disease.
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PMID:Leucine-rich repeat-containing G-protein-coupled receptor 8 in the rat brain: Enrichment in thalamic neurons and their efferent projections. 1870 79

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

Clinical evidence has shown a correlation between Parkinson's disease (PD) and Type 2 Diabetes (T2D), as abnormal glucose tolerance has been reported in >50% of PD patients. The development of insulin resistance and the degeneration of nigrostriatal dopamine (DA) neurons are both mediated by oxidative mechanisms, and oxidative stress is likely a mechanistic link between these pathologies. Although glucose uptake in neuronal tissues is primarily non-insulin dependent, proteins involved in insulin signaling, such as insulin receptor substrate 2 (IRS2) and glucose transporter 4 (GLUT4), are present in the basal ganglia. The purpose of this study was to determine whether nigrostriatal DA depletion affects measures of insulin resistance in the striatum. Six weeks after 6-hydroxydopamine (6-OHDA) infusion into the medial forebrain bundle, rats were classified as having either partial (20-65%) or severe (90-99%) striatal DA depletion. Increased IRS2 serine phosphorylation, a marker of insulin resistance, was observed in the DA-depleted striatum. Additionally, severe depletion resulted in decreased total IRS2, indicating possible degradation of the protein. Decreased phosphorylation of AKT and expression of the kinase glycogen synthase kinase-3 alpha (GSK3-alpha) was also measured in the striatum of severely DA-depleted animals. Finally, expression of heat shock protein 25 (Hsp25), which is protective against oxidative damage and can decrease stress kinase activity, was decreased in the striatum of lesioned rats. Together, these results support the hypothesis that nigrostriatal DA depletion impairs insulin signaling in the basal ganglia.
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PMID:Measures of striatal insulin resistance in a 6-hydroxydopamine model of Parkinson's disease. 1880 3

Alzheimer's disease (AD) is a progressive neurodegenerative disease for which there are few therapeutic regimens that influence the underlying pathogenic phenotypes. However, of the currently available therapies, exercise training is considered to be one of the best candidates for amelioration of the pathological phenotypes of AD. Therefore, we directly investigated exercise training to determine whether it was able to ameliorate the molecular pathogenic phenotypes in the brain using a neuron-specific enolase (NSE)/Swedish mutation of amyloid precursor protein (APPsw) transgenic (Tg) mice as a novel AD model. To accomplish this, Non-Tg and NSE/ APPsw Tg mice were subjected to exercise on a treadmill for 16 weeks, after which their brains were evaluated to determine whether any changes in the pathological phenotype-related factors had occurred. The results indicated (i) that amyloid beta-42 (Abeta-42) peptides were significantly decreased in the NSE/APPsw Tg mice following exercise training; (ii) that exercise training inhibited the apoptotic biochemical cascades, including cytochrome c, caspase-9, caspase-3 and Bax; (iii) that the glucose transporter-1 (GLUT-1) and brain-derived neurotrophic factor (BDNF) proteins induced by exercise training protected the neurons from injury by inducing the concomitant expression of genes that encode proteins such as superoxide dismutase-1 (SOD-1), catalase and Bcl-2, which suppress oxidative stress and excitotoxic injury; (iv) that heat-shock protein-70 (HSP-70) and glucose-regulated protein-78 (GRP-78) were significantly increased in the exercise (EXE) group when compared to the sedentary (SED) group, and that these proteins may benefit the brain by making it more resistant to stress-induced neuron cell damage; (v) and that exercise training contributed to the restoration of normal levels of serum total cholesterol, insulin and glucose. Taken together, these results suggest that exercise training represents a practical therapeutic strategy for human subjects suffering from AD. Moreover, this training has the potential for use in new therapeutic strategies for the treatment of other chronic disease including diabetes, cardiovascular and Parkinson's disease.
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PMID:Exercise training acts as a therapeutic strategy for reduction of the pathogenic phenotypes for Alzheimer's disease in an NSE/APPsw-transgenic model. 1881 61

Gene expression changes in neuropsychiatric and neurodegenerative disorders, and gene responses to therapeutic drugs, provide new ways to identify central nervous system (CNS) targets for drug discovery. This review summarizes gene and pathway targets replicated in expression profiling of human postmortem brain, animal models, and cell culture studies. Analysis of isolated human neurons implicates targets for Alzheimer's disease and the cognitive decline associated with normal aging and mild cognitive impairment. In addition to tau, amyloid-beta precursor protein, and amyloid-beta peptides (Abeta), these targets include all three high-affinity neurotrophin receptors and the fibroblast growth factor (FGF) system, synapse markers, glutamate receptors (GluRs) and transporters, and dopamine (DA) receptors, particularly the D2 subtype. Gene-based candidates for Parkinson's disease (PD) include the ubiquitin-proteosome system, scavengers of reactive oxygen species, brain-derived neurotrophic factor (BDNF), its receptor, TrkB, and downstream target early growth response 1, Nurr-1, and signaling through protein kinase C and RAS pathways. Increasing variability and decreases in brain mRNA production from middle age to old age suggest that cognitive impairments during normal aging may be addressed by drugs that restore antioxidant, DNA repair, and synaptic functions including those of DA to levels of younger adults. Studies in schizophrenia identify robust decreases in genes for GABA function, including glutamic acid decarboxylase, HINT1, glutamate transport and GluRs, BDNF and TrkB, numerous 14-3-3 protein family members, and decreases in genes for CNS synaptic and metabolic functions, particularly glycolysis and ATP generation. Many of these metabolic genes are increased by insulin and muscarinic agonism, both of which are therapeutic in psychosis. Differential genomic signals are relatively sparse in bipolar disorder, but include deficiencies in the expression of 14-3-3 protein members, implicating these chaperone proteins and the neurotransmitter pathways they support as possible drug targets. Brains from persons with major depressive disorder reveal decreased expression for genes in glutamate transport and metabolism, neurotrophic signaling (eg, FGF, BDNF and VGF), and MAP kinase pathways. Increases in these pathways in the brains of animals exposed to electroconvulsive shock and antidepressant treatments identify neurotrophic and angiogenic growth factors and second messenger stimulation as therapeutic approaches for the treatment of depression.
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PMID:Target identification for CNS diseases by transcriptional profiling. 1892 5

Endosulfine-alpha (ENSA) is a 121-residue cAMP-regulated phosphoprotein, originally identified as an endogenous regulator of ATP-sensitive potassium channels. ENSA has been implicated in the regulation of insulin secretion, and expression of ENSA is decreased in brains of both Alzheimer's disease (AD) and Down's syndrome patients. We recently described membrane-dependent interactions between ENSA and the Parkinson's disease associated protein alpha-synuclein. Here we characterize the conformational change in ENSA that occurs upon binding to membranes. Secondary chemical shift analysis demonstrates formation of four helices in the lipid-bound state that are not present in the absence of lipid. The helical structure is maintained in several different lipid mimetics (sodium dodecyl sulfate, dodecyl phosphocholine, lyso 1-palmitoyl phosphatidylglycerol, and phospholipid vesicles). Introduction of a mutation (S109E) to mimic PKA phosphorylation of ENSA leads to a perturbation of the fourth helix and disrupts the interaction with alpha-synuclein. These data establish ENSA as an intrinsically unstructured protein that adopts a stable structure upon membrane binding, properties it shares with its binding partner alpha-synuclein.
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PMID:Membrane-induced folding of the cAMP-regulated phosphoprotein endosulfine-alpha. 1897 46

Embryonic stem cells (ESC) hold the promise of overcoming many diseases as potential sources of, for example, dopaminergic neural cells for Parkinson's Disease to pancreatic islets to relieve diabetic patients of their daily insulin injections. While an embryo has the innate capacity to develop fully functional differentiated tissues; biologists are finding that it is much more complex to derive singular, pure populations of primary cells from the highly versatile ESC from this embryonic parent. Thus, a substantial investment in developing the technologies to expand and differentiate these cells is required in the next decade to move this promise into reality. In this review we document the current standard assays for characterising human ESC (hESC), the status of 'defined' feeder-free culture conditions for undifferentiated hESC growth, examine the quality controls that will be required to be established for monitoring their growth, review current methods for expansion and differentiation, and speculate on the possible routes of scaling up the differentiation of hESC to therapeutic quantities.
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PMID:Human embryonic stem cell technology: large scale cell amplification and differentiation. 1900 78

Glucagon-like peptide-1 (GLP-1) is an endogenous insulinotropic peptide secreted from the gastrointestinal tract in response to food intake. It enhances pancreatic islet beta-cell proliferation and glucose-dependent insulin secretion, and lowers blood glucose and food intake in patients with type 2 diabetes mellitus (T2DM). A long-acting GLP-1 receptor (GLP-1R) agonist, exendin-4 (Ex-4), is the first of this new class of antihyperglycemia drugs approved to treat T2DM. GLP-1Rs are coupled to the cAMP second messenger pathway and, along with pancreatic cells, are expressed within the nervous system of rodents and humans, where receptor activation elicits neurotrophic actions. We detected GLP-1R mRNA expression in both cultured embryonic primary cerebral cortical and ventral mesencephalic (dopaminergic) neurons. These cells are vulnerable to hypoxia- and 6-hydroxydopamine-induced cell death, respectively. We found that GLP-1 and Ex-4 conferred protection in these cells, but not in cells from Glp1r knockout (-/-) mice. Administration of Ex-4 reduced brain damage and improved functional outcome in a transient middle cerebral artery occlusion stroke model. Ex-4 treatment also protected dopaminergic neurons against degeneration, preserved dopamine levels, and improved motor function in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD). Our findings demonstrate that Ex-4 can protect neurons against metabolic and oxidative insults, and they provide preclinical support for the therapeutic potential for Ex-4 in the treatment of stroke and PD.
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PMID:GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. 1916 83

A new generation of multifunctional fusion proteins presents a potential solution to overcome the challenges associated with brain drug delivery and development of treatments for neurological disorders, including stroke, Alzheimer's disease, Parkinson's disease and inherited mucopolysaccharidosis. These biotherapeutics are engineered i) to cross the blood-brain barrier (BBB) following i.v. administration and ii) to produce a brain therapeutic effect. These fusion proteins are comprised of both a transport and a therapeutic domain. The transport domain is a monoclonal antibody (MAb) directed to an exofacial epitope of the BBB human insulin receptor (HIR), which uses the BBB endogenous insulin transport system to gain access to the brain via receptor-mediated transcytosis without interfering with the normal transport of insulin. Both human-chimeric and fully humanized versions of the anti-human HIRMAb have already been produced. The therapeutic domain of these fusion proteins consists of the peptide or protein of interest fused to the carboxyl terminus of the C(H)3 region of the heavy chain of the anti-human HIRMAb. A variety of HIRMAb fusion proteins were engineered aiming at the development of therapeutics for the central nervous system (CNS), i.e., stroke and Parkinson's disease, as in the case of HIRMAb-BDNF and HIRMAb-GDNF, respectively, HIRMAb-IDUA for the treatment of Hurler's disease, HIRMAb-A beta single chain antibody for passive immunotherapy of Alzheimer's disease, and HIRMAb-avidin as delivery system for biotinylated drugs, like siRNAs. The multifunctionality of these fusion proteins has been validated in preclinical work, including brain update in primates. Pending further development into pharmacological and toxicological studies, and clinical trials, members of the biotherapeutic family discussed in the present review, designed to overcome the brain drug delivery hurdle, are positioned to become a new generation of neuropharmaceutical drugs for the treatment of human CNS disorders.
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PMID:A new generation of neurobiological drugs engineered to overcome the challenges of brain drug delivery. 1918 Feb 67

Rosiglitazone is a commonly prescribed insulin-sensitizing drug with a selective agonistic activity on the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). PPAR-gamma can modulate inflammatory responses in the brain, and agonists might be beneficial in neurodegenerative diseases. In the present study we used a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine plus probenecid (MPTPp) mouse model of progressive Parkinson's disease (PD) to assess the therapeutic efficacy of rosiglitazone on behavioural impairment, neurodegeneration and inflammation. Mice chronically treated with MPTPp displayed typical features of PD, including impairment of motor and olfactory functions associated with partial loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNc), decrease of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) content and dynorphin (Dyn) mRNA levels in the caudate-putamen (CPu), intense microglial and astroglial response in the SNc and CPu. Chronic rosiglitazone, administered in association with MPTPp, completely prevented motor and olfactory dysfunctions and loss of TH-positive cells in the SNc. In the CPu, loss of striatal DA was partially prevented, whereas decreases in DOPAC content and Dyn were fully counteracted. Moreover, rosiglitazone completely inhibited microglia reactivity in SNc and CPu, as measured by CD11b immunostaining, and partially inhibited astroglial response assessed by glial fibrillary acidic protein immunoreactivity. Measurement of striatal MPP+ levels 2, 4, 6 h and 3 days after chronic treatment indicated that MPTP metabolism was not altered by rosiglitazone. The results support the use of PPAR-gamma agonists as a putative anti-inflammatory therapy aimed at arresting PD progression, and suggest that assessment in PD clinical trials is warranted.
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PMID:PPAR-gamma-mediated neuroprotection in a chronic mouse model of Parkinson's disease. 1924 67


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