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)

The molecular basis for the known intramembrane receptor/receptor interactions among G protein-coupled receptors was postulated to be heteromerization based on receptor subtype-specific interactions between different types of receptor homomers. The discovery of GABAB heterodimers started this field rapidly followed by the discovery of heteromerization among isoreceptors of several G protein-coupled receptors such as delta/kappa opioid receptors. Heteromerization was also discovered among distinct types of G protein-coupled receptors with the initial demonstration of somatostatin SSTR5/dopamine D2 and adenosine A1/dopamine D1 heteromeric receptor complexes. The functional meaning of these heteromeric complexes is to achieve direct or indirect (via adapter proteins) intramembrane receptor/receptor interactions in the complex. G protein-coupled receptors also form heteromeric complexes involving direct interactions with ion channel receptors, the best example being the GABAA/dopamine D5 receptor heteromerization, as well as with receptor tyrosine kinases and with receptor activity modulating proteins. As an example, adenosine, dopamine, and glutamate metabotropic receptor/receptor interactions in the striatopallidal GABA neurons are discussed as well as their relevance for Parkinson's disease, schizophrenia, and drug dependence. The heterodimer is only one type of heteromeric complex, and the evidence is equally compatible with the existence of higher order heteromeric complexes, where also adapter proteins such as homer proteins and scaffolding proteins can exist. These complexes may assist in the process of linking G protein-coupled receptors and ion channel receptors together in a receptor mosaic that may have special integrative value and may constitute the molecular basis for some forms of learning and memory.
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PMID:Molecular mechanisms and therapeutical implications of intramembrane receptor/receptor interactions among heptahelical receptors with examples from the striatopallidal GABA neurons. 1286 60

Mammalian motor activity displays circadian patterns in normal behaviour and in many movement disorders, like levodopa responsive dystonia and Parkinson's disease. Here, we hypothesized that a circadian pattern of dopamine synthesis would trigger rhythms in the expression of genes in regions receiving dopaminergic innervation. Indeed tyrosine hydroxylase and cholecystokinin mRNA were upregulated in the substantia nigra and ventral tegmental area in the course of the day. However, in the caudate putamen, the mRNA levels, for dopamine D2 and adenosine 2A receptor, dynorphin, and substance P were lower during the day than during the night, whereas the expression of dopamine D1 receptor, enkephalin, and somatostatin was stable. In the frontal cortex, a clear midday peak of enkephalin expression was detected, while cholecystokinin and vasoactive intestinal peptide expression did not vary. Clear circadian gene expression patterns can therefore be demonstrated in brain regions involved in motor regulation, but they do not follow a simple dopaminergic drive and more complex regulatory patterns have to be assumed.
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PMID:Circadian patterns of neurotransmitter related gene expression in motor regions of the rat brain. 1501 24

Ascorbic acid (AA) has been shown to increase the yield of dopaminergic (DA) neurons derived from basic fibroblast growth factor (bFGF)-expanded mesencephalic precursors. To understand the molecular mechanisms underlying this phenomenon, we used cDNA microarray analysis to examine differential expression of neuronal genes following AA treatment. The putative precursor cells were isolated from E13 rat ventral mesencephalons and expanded in the presence of bFGF. Cells were incubated in mitogen-free media supplemented with 200 microM AA or were left untreated as a control, and total RNA was isolated at different time points (expansion stage and 1, 3, and 6 days after induction of differentiation) and subjected to cDNA microarray analysis. Differentiation was evaluated by Western blot analysis and immunocytochemistry of neuron-specific markers. AA treatment of the mesencephalic precursors increased the expression of neuronal (MAP2) and astrocytic (glial fibrillary acidic protein) markers and the percentage of tyrosine hydroxylase (TH)-positive cells. The microarray analysis revealed that 12 known genes were up-regulated and 20 known genes were down-regulated in expansion-stage AA-treated cells. Six days after the induction of differentiation, AA-treated cells showed up-regulation of 48 known genes and down-regulation of 5 known genes. Our results identified several proteins, such as transferrin, S-100, and somatostatin, as being differentially regulated in AA-treated mesencephalic precursors. This novel result may lead to a better understanding of the molecular mechanisms underlying the AA-induced differentiation of mesencephalic precursors into DA neurons and may form the basis for improved DA neuronal production for treatment of Parkinson's disease patients.
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PMID:Changes of gene expression profiles during neuronal differentiation of central nervous system precursors treated with ascorbic acid. 1537 4

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

This review analyzes current evidence regarding possible mechanisms of nigral damage in idiopathic Parkinson's disease (iPD). In normal brain, a specific interplay among the blood-brain barrier (BBB), substantia nigra (SN), and locus coeruleus (LC) creates the condition for a self-accelerating damage to the SN. Three vicious circles involving SN-BBB, LC-SN-BBB, and histamine-BBB-SN interactions are described. In iPD, a self-accelerating loss of nigral cells can be triggered by brain hypoperfusion and by an increased blood histamine level. iPD-associated factors such as decreased CSF levels of substance P, somatostatin, and glutamate can aggravate the vicious-circle-induced damage to the SN.
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PMID:Self-amplification of nigral degeneration in Parkinson's disease: a hypothesis. 1893 18

The principal causative pathology of Parkinson disease is the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta projecting to the striatum in the brain. The information regarding the expression of neuropeptides in parkinsonism is very limited. Here we have elucidated striatal neuropeptide mechanisms in experimental parkinsonism using the unilateral 6-hydroxydopamine model to degenerate dopamine neurons. A thoroughly controlled sample preparation technique together with a peptidomics approach and targeted neuropeptide sequence collections enabled sensitive detection, identification, and relative quantitation of a great number of endogenous neuropeptides. Previously not recognized alterations in neuropeptide levels were identified in the unilateral lesioned mice with or without subchronic 3,4-dihydroxy-L-phenylalanine administration, the conventional treatment of Parkinson disease. Several of these peptides originated from the same precursor such as secretogranin-1, somatostatin, prodynorphin, and cholecystokinin. Disease-related biotransformation of precursors into individual peptides was observed in the experimental model of Parkinson disease. Several previously unreported potentially biologically active peptides were also identified from the striatal samples. This study provides further evidence that neuropeptides take part in mediating the central nervous system failure associated with Parkinson disease.
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PMID:Striatal alterations of secretogranin-1, somatostatin, prodynorphin, and cholecystokinin peptides in an experimental mouse model of Parkinson disease. 1913 25

G-protein-coupled receptors (GPCRs) exist both as monomers and also as dimers or higher-order oligomers, representing assemblies either with their peers or with other classes of GPCR ("heterodimers"). The pharmacological profiles of heterodimers often differ from the corresponding monomers or homodimers. Heterodimerization of dopamine receptors has been shown for both the D1/D5 and D2/D3/D4 receptor families, which couple positively and negatively, respectively, to adenylyl cyclase. Notably, heterodimers are formed by: D1 and adenosine A1 receptors; D2 or D3 and adenosine A2 receptors; and D2 and somatostatin SST5 receptors. Further, D1, D2 and D3 receptors physically assemble into functional D1/D2, D1/D3 and D2/D3 heterodimers possessing binding and coupling profiles distinct from the respective monomers. This article reviews data on dopamine D3/D2 and D3/D1 heterodimers, including observations that some antiparkinsonian agents--such as the preferential high-efficacy D3 versus D2 receptor agonists, pramipexole and ropinirole--show amplified potency at D3/D2 heterodimers versus constituent monomers, and others in contrast, such as the D3/D2 receptor agonist pergolide, show no difference. This article also discusses allosteric modulation amongst heterodimeric dopamine receptors, whereby agonist actions at one member of a heterodimer influence functional coupling at the other protomer. Finally, it presents data showing that, in cells co-transfected with D3 and D1 receptors, long-term exposure to pramipexole and ropinirole (which possess negligible affinities for D1 sites) elicits supersensitivity of D1 receptor-activated adenylyl cyclase, and conversely, D3/D2 receptor agonists such as apomorphine and bromocriptine (which also act as D1 receptor agonists) do not. A hypothetical relationship between these observations and the exacerbation of gambling in Parkinson's disease by antiparkinsonian agents is discussed.
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PMID:Heterodimerization of dopamine receptors: new insights into functional and therapeutic significance. 2012 51

Hyposmia is an early symptom of idiopathic Parkinson's disease but the pathological bases of such dysfunction are largely unknown. The distribution of alpha-synuclein, which forms Lewy bodies and Lewy neurites, and the types of neurons (based on their neurotransmitters) affected by alpha-synucleinopathy were investigated in the olfactory system in Parkinson's disease. Immunohistochemical distribution of alpha-synuclein and its co-localization with tyrosine hydroxylase, somatostatin, calbindin, calretinin, parvalbumin and substance P in the olfactory bulb, anterior olfactory nucleus, olfactory tubercle and piriform, periamygdaloid and rostral entorhinal cortices of idiopathic Parkinson's disease cases (n = 11) and age-matched controls (n = 11) were investigated. Lewy bodies and Lewy neurites were present in the olfactory bulb, particularly in mitral cells and in the inner plexiform layer. alpha-synuclein was particularly abundant in the different divisions of the anterior olfactory nucleus (bulbar, intrapeduncular, retrobulbar and cortical). In contrast, Lewy bodies and Lewy neurites were less abundant in the olfactory tubercle and olfactory cortices. In the olfactory bulb, anterior olfactory nucleus and olfactory cortices, cells affected by alpha-synucleinopathy rarely co-localized tyrosine hydroxylase or somatostatin, but they frequently co-localized calbindin, calretinin, parvalbumin and substance P. The present data provide evidence that alpha-synucleinopathy affects neurons along the olfactory pathway. Dopamine- and somatostatin-positive cells are rarely affected; whereas the cell types most vulnerable to neurodegeneration include glutamate- (mitral cells), calcium-binding protein- and substance P-positive cells. These results provide data on the distribution and cell types involved by alpha-synucleinopathy in the human olfactory system during Parkinson disease that may be useful for future clinical investigation.
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PMID:alpha-Synucleinopathy in the human olfactory system in Parkinson's disease: involvement of calcium-binding protein- and substance P-positive cells. 2038 14

Pituitary adenomas are associated with a variety of clinical manifestations resulting from excessive hormone secretion and tumor mass effects, and require a multidisciplinary management approach. This article discusses the treatment modalities for the management of patients with a prolactinoma, Cushing's disease and acromegaly, and summarizes the options for medical therapy in these patients.First-line treatment of prolactinomas is pharmacotherapy with dopamine agonists; recent reports of cardiac valve abnormalities associated with this class of medication in Parkinson's disease has prompted study in hyperprolactinemic populations. Patients with resistance to dopamine agonists may require other treatment.First-line treatment of Cushing's disease is pituitary surgery by a surgeon with experience in this condition. Current medical options for Cushing's disease block adrenal cortisol production, but do not treat the underlying disease. Pituitary-directed medical therapies are now being explored. In several small studies, the dopamine agonist cabergoline normalized urinary free cortisol in some patients. The multi-receptor targeted somatostatin analogue pasireotide (SOM230) shows promise as a pituitary-directed medical therapy in Cushing's disease; further studies will determine its efficacy and safety. Radiation therapy, with medical adrenal blockade while awaiting the effects of radiation, and bilateral adrenalectomy remain standard treatment options for patients not cured with pituitary surgery.In patients with acromegaly, surgery remains the first-line treatment option when the tumor is likely to be completely resected, or for debulking, especially when the tumor is compressing neurovisual structures. Primary therapy with somatostatin analogues has been used in some patients with large extrasellar tumors not amenable to surgical cure, patients at high surgical risk and patients who decline surgery. Pegvisomant is indicated in patients who have not responded to surgery and other medical therapy, although there are regional differences in when it is prescribed.In conclusion, the treatment of patients with pituitary adenomas requires a multidisciplinary approach. Dopamine agonists are an effective first-line medical therapy in most patients with a prolactinoma, and somatostatin analogues can be used as first-line therapy in selected patients with acromegaly. Current medical therapies for Cushing's disease primarily focus on adrenal blockade of cortisol production, although pasireotide and cabergoline show promise as pituitary-directed medical therapy for Cushing's disease; further long-term evaluation of efficacy and safety is important.
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PMID:Prolactinomas, Cushing's disease and acromegaly: debating the role of medical therapy for secretory pituitary adenomas. 2047 50

GABAergic interneurons modulate cortical activity through the actions of distinct subgroups. Recent studies using interneuron transplants have shown tremendous promise as cell-based therapies for seizure disorders, Parkinson's disease, and in the study of neocortical plasticity. Previous reports identified a spatial bias for the origins of parvalbumin (PV)- and somatostatin (SST)-expressing interneuron subgroups within the medial ganglionic eminence (MGE). In the current study, the mitotic origins of these interneurons are examined by harvesting MGE cells at 2 time points and evaluating their neurochemical profiles after transplantation into neonatal mouse cortex. Although the dorsal MGE (dMGE)-SST and ventral MGE (vMGE)-PV bias were confirmed, both subgroups originate from progenitors located throughout the MGE. The dMGE bias was also found for SST subgroups that coexpress calretinin or reelin. In contrast, another major subgroup of SST interneuron, neuropeptide Y-expressing, does not appear to originate within the MGE. Finally, novel evidence is provided that a clinically important subtype of PV-expressing interneuron, the chandelier (axo-axonic) cell, is greatly enriched in transplants from the vMGE at embryonic day 15. These findings have important implications both for the study of interneuron fate determination and for studies that use interneuron precursor transplantation to alter cortical activity.
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PMID:Spatial and temporal bias in the mitotic origins of somatostatin- and parvalbumin-expressing interneuron subgroups and the chandelier subtype in the medial ganglionic eminence. 2169 85


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