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)

Mutations in the DJ-1 gene have been implicated in the autosomal recessive early onset parkinsonism. DJ-1 is a soluble dimeric protein with critical roles in response to oxidative stress and in neuronal maintenance. However, several lines of evidence suggest the existence of a nonfunctional aggregated form of DJ-1 in the brain of patients with some neurodegenerative diseases. Here, we show that inorganic phosphate, an important anion that exhibits elevated levels in patients with Parkinson disease, transforms DJ-1 into filamentous aggregates. According to the 2.4-A crystal structure, DJ-1 dimers are linearly stacked through P(i)-mediated interactions to form protofilaments, which are then bundled into a filamentous assembly.
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PMID:Crystal structure of filamentous aggregates of human DJ-1 formed in an inorganic phosphate-dependent manner. 1892 3

Growth factor therapy for Parkinson's disease offers the prospect of restoration of dopaminergic innervation and/or prevention of neurodegeneration. Safety and efficacy of an adeno-associated virus (AAV2) encoding human glial cell-derived neurotrophic factor (GDNF) was investigated in aged nonhuman primates. Positron emission tomography with 6-[(18)F]-fluoro-l-m-tyrosine (FMT-PET) in putamen was assessed 3 months before and after AAV2 infusion. In the right putamen, monkeys received either phosphate-buffered saline or low-dose (LD) or high-dose (HD) AAV2-GDNF. Monkeys that had received putaminal phosphate-buffered saline (PBS) infusions additionally received either PBS or HD AAV2-GDNF in the right substantia nigra (SN). The convection-enhanced delivery method used for infusion of AAV2-GDNF vector resulted in robust volume of GDNF distribution within the putamen. AAV2-GDNF increased FMT-PET uptake in the ipsilateral putamen as well as enhancing locomotor activity. Within the putamen and caudate, the HD gene transfer mediated intense GDNF fiber and extracellular immunoreactivity (IR). Retrograde and anterograde transport of GDNF to other brain regions was observed. AAV2-GDNF did not significantly affect dopamine in the ipsilateral putamen or caudate, but increased dopamine turnover in HD groups. HD putamen treatment increased the density of dopaminergic terminals in these regions. HD treatments, irrespective of the site of infusion, increased the number of nonpigmented TH-IR neurons in the SN. AAV2-GDNF gene transfer does not appear to elicit adverse effects, delivers therapeutic levels of GDNF within target brain areas, and enhances utilization of striatal dopamine and dopaminergic nigrostriatal innervation.
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PMID:Clinically relevant effects of convection-enhanced delivery of AAV2-GDNF on the dopaminergic nigrostriatal pathway in aged rhesus monkeys. 1920 43

We investigated the safety and neuroregenerative potential of an adeno-associated virus (AAV2) containing human glial cell line-derived neurotrophic factor (GDNF) in an MPTP primate model of Parkinson's disease. Dopaminergic function was evaluated by positron emission tomography with 6-[(18)F]fluoro-l-m-tyrosine (FMT) before and after AAV2-GDNF or phosphate-buffered saline infusion bilaterally into the putamen. FMT uptake was significantly increased bilaterally in the putamen of AAV2-GDNF but not phosphate-buffered saline-treated animals 6 months after infusion, indicating increased dopaminergic activity in the nigrostriatal pathways. AAV2-GDNF-treated animals also showed clinical improvement without adverse effects. These findings are consistent with our previous report in aged nonhuman primates that showed evidence of enhanced use of striatal dopamine and dopaminergic nigrostriatal innervation. Clinical improvement and evidence of functional recovery in the nigrostriatal pathway, and the absence of adverse effects, support the safety of this approach for the delivery of GDNF over a 6-month period.
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PMID:Functional effects of AAV2-GDNF on the dopaminergic nigrostriatal pathway in parkinsonian rhesus monkeys. 1925 73

The health-relevant functionality of Mucuna pruriens was improved by priming the seeds with elicitors of the pentose phosphate pathway (PPP) such as fish protein hydrolysates (FPHs), lactoferrin (LF) and oregano extract (OE) followed by dark germination. FPH elicited the highest phenolic content of 19 mg/g FW on day 1, which was 38% higher than control sprouts. OE enhanced Parkinson's disease-relevant L-DOPA content by 33% on day 1 compared to control sprouts. Anti-diabetes-relevant alpha-amylase inhibition percent (AIP) and alpha-glucosidase inhibition percent (GIP) were high in the cotyledons and decreased following elicitation and sprouting. For potential anti-diabetic applications, low AIP and high GIP with moderate L-DOPA content on day 4 of dark germination could be optimal. Improved L-DOPA concentrations in a soluble phenolic and antioxidant-rich M. pruriens background on day 1 sprouts have potential for Parkinson's disease management.
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PMID:Improved health-relevant functionality in dark germinated Mucuna pruriens sprouts by elicitation with peptide and phytochemical elicitors. 1945 56

The intramembrane receptor-receptor interactions among GPCRs demonstrated in the beginning of the 80s in the CNS probably reflect the existence of allosteric mechanisms in receptor heteromers, and the postulated assemblies of multiple GPCRs coined 'receptor mosaics' in the early 80s probably represent higher order receptor heteromers, recently demonstrated with novel biophysical techniques in living cells. The receptor interface in the GPCR heteromers is beginning to be characterized and in adenosine A(2A)-dopamine D(2)-like heteromers the electrostatic arginine-phosphate salt bridge seems to be a hot spot in the interface with covalent-like stability, possibly participating in the allosteric interactions and making possible integration of heteromer receptor function. We discuss the possible relevance of some putative D(2) receptor heteromers in the treatment of Parkinson's disease and schizophrenia, respectively.
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PMID:Molecular integration via allosteric interactions in receptor heteromers. A working hypothesis. 1994 81

Mitochondrial dysfunction hypothetically contributes to neuronal degeneration in patients with Parkinson's disease. While several in vitro data exist, the measurement of cerebral mitochondrial dysfunction in living patients with Parkinson's disease is challenging. Anatomical magnetic resonance imaging combined with phosphorus and proton magnetic resonance spectroscopic imaging provides information about the functional integrity of mitochondria in specific brain areas. We measured partial volume corrected concentrations of low-energy metabolites and high-energy phosphates with sufficient resolution to focus on pathology related target areas in Parkinson's disease. Combined phosphorus and proton magnetic resonance spectroscopic imaging in the mesostriatal region was performed in 16 early and 13 advanced patients with Parkinson's disease and compared to 19 age-matched controls at 3 Tesla. In the putamen and midbrain of both Parkinson's disease groups, we found a bilateral reduction of high-energy phosphates such as adenosine triphophosphate and phosphocreatine as final acceptors of energy from mitochondrial oxidative phosphorylation. In contrast, low-energy metabolites such as adenosine diphophosphate and inorganic phosphate were within normal ranges. These results provide strong in vivo evidence that mitochondrial dysfunction of mesostriatal neurons is a central and persistent phenomenon in the pathogenesis cascade of Parkinson's disease which occurs early in the course of the disease.
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PMID:Phosphorus and proton magnetic resonance spectroscopy demonstrates mitochondrial dysfunction in early and advanced Parkinson's disease. 1995 56

Intracytoplasmic alpha-synuclein (alpha-syn) amyloidogenic inclusions are a major pathological feature of Parkinson's disease, dementia with Lewy body disease and multiple systems atrophy. The mechanisms involved in the formation and inhibition of these aggregates are areas of intense investigation. The present study characterizes a novel cellular model for the study of alpha-syn aggregation, incorporating nucleation-dependent aggregation and a new function for calcium phosphate precipitation. Cultured cells were readily induced to develop large, cytoplasmic alpha-syn filamentous aggregates that were hyperphosphorylated, often ubiquitinated and thioflavin positive. These cellular aggregates formed in the majority of transfected cells and recruited approximately half of endogenously expressed alpha-syn. Using this system, we examined single-point mutations that inhibit alpha-syn amyloid formation in vitro. Three mutations (V66P, T72P and T75P) significantly hindered alpha-syn aggregation in this cell model. The T75P mutant, which could abrogate amyloid formation of wild-type alpha-syn in vitro, did not prevent wild-type alpha-syn cellular aggregates. These studies suggest that the propensity of alpha-syn to form cellular aggregates may be more pronounced than in isolated in vitro studies. This novel high-efficiency cellular model of alpha-syn aggregation is a valuable system that may be used to further understand alpha-syn aggregation and allow for the generation of future therapeutics.
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PMID:A novel, high-efficiency cellular model of fibrillar alpha-synuclein inclusions and the examination of mutations that inhibit amyloid formation. 2013 85

The trace elements of scalp hair samples from > or =60-year-old dementia patients and normal persons have been studied by X-ray absorption near-edge spectroscopy (XANES) in fluorescent mode and wavelength-dispersive X-ray fluorescence spectrometry. Comparisons of hair trace element levels of age-matched dementia patients and normal persons revealed significantly elevated amounts of calcium, chlorine and phosphorus in dementia patients relative to normal persons. The results of XANES measurements identify the chemical forms of deposited calcium and phosphorus in the hair samples of both dementia patients and normal persons to be calcium chloride (CaCl(2)) and phosphate (PO(4)(3-)), respectively. The amount of sulfur in hairs of dementia patients was found to be not significantly different from that in normal persons. The sulfur K-edge XANES spectra, however, show significantly higher accumulations of sulfur in the sulfate (SO(4)(2-)) form in hairs of Alzheimer's disease and Parkinson's disease dementia patients. This study presents the possible roles of calcium, chlorine, phosphorus and sulfur in the etiology of dementia in elderly patients.
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PMID:Trace element analysis of hairs in patients with dementia. 2015 82

Disorders of the function of the tyrosine hydroxylase play an important role in the occurrence of the Parkinson syndrome. The enzyme that catalyses the first, rate-limiting step in the biosynthesis to dopamine requires the cofactor tetrahydrobiopterin. This compound supplies the reduction equivalent for activation of molecular oxygen. Binding of the cofactor to the enzyme is affected by phosphorylation or dephosphorylation of the enzyme protein and, thereby, influences the activity. Nerve and chromaffin cells that synthesize dopamine, noradrenaline and serotonin are able to synthesize the cofactor tetrahydrobiopterin de novo from guanosine-triphosphate as a precursor. In patients suffering from Parkinson's disease a remarkable decrease in biopterin content was found in the brain. The function of the dopaminergic system was studied with an experimental Parkinson model. The antimetabolite 6-aminonicotinamide induces a dopamine deficit in the striatum with a significant slowdown in the utilization of this transmitter. The abolition of the 6-aminonicotinamide-induced muscular rigidity by l-DOPA and dopamine agonists implies that the antimetabolite produces a Parkinson-like syndrome in rats. There are reports on the molecular basis of this effect which are also important for understanding possible disturbances of the synthesis of biopterins. The effector 6-aminonicotinamide-adenine-dinucleotide-phosphate (6-ANADP), which blocks the pentose phosphate pathway, is formed by an enzymatic neurotoxic synthesis. The clonal cell line PC-12 was used to study the molecular basis of the disturbances occurring in the dopaminergic system. These cells contain all the enzymes for catecholamine synthesis, including those for the synthesis of the cofactor tetrahydrobiopterin. Addition of 6-aminonicotinamide to the culture medium resulted in the synthesis of the neurotoxic agent, 6-ANADP, by a glycohydrolase localized in the endoplasmic reticulum. The synthesis of biopterin was depressed after application of 6-aminonicotinamide. The decrease of intracellular tetrahydrobiopterin and total biopterin resulted in reduced DOPA production. The decreased content of biopterin cofactor synthesis was compensated for by the addition of the precursor sepiapterin, indicating that the NADPH-dependent reductases in biopterin synthesis were not inhibited by the antimetabolic nucleotide 6-ANADP. DOPA production was not fully normalized by sepiapterin. Addition of NADH to the medium resulted in a further increase of DOPA production, probably by activation of the recycling pathway. The first step in the synthesis of biopterin from GTP to 7,8-neopterin-triphosphate seems to be particularly sensitive to the action of exogenous neurotoxins. A further sensitive site of action in synthesis to the cofactor BH(4) concerns the function of the dihydropteridin-reductase, which recycles qBH(2) to BH(4). Neurotoxin-induced impairment of biopterin synthesis is probably a pathogenetically important disorder at the initial stage of Parkinson's disease.
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PMID:Neurotoxin-induced impairment of biopterin synthesis and function: Initial stage of a Parkinson-like dopamine deficiency syndrome. 2050 23

Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder of mature and older individuals. Since all aged individuals do not develop PD, predisposing conditions may exist that pair with the stress placed on the basal ganglia during aging to produce the symptoms of PD. In this project we used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to test the hypothesis that a sensitization stage and a precipitating stage underlie idiopathic PD. To induce the sensitization stage, pregnant C57BL/6J mice were treated with MPTP (10 mg/kg/day) during gestation days 8-12 to target the emerging fetal nigrostriatal dopamine neurons. For the precipitating stage, the 3-months old offspring were administered MPTP for 7 days, to simulate the changes that occur during aging. The weights and motor activity of the offspring, high performance liquid chromatography (HPLC) striatal dopamine and its metabolites and Western blot for tyrosine hydroxylase (TH) were determined. Offspring exposed to prenatal MPTP showed lower birth weights that eventually recovered. Prenatal MPTP also reduced motor activity by 10-30%, striatal TH by 38%, dopamine by 14%, homovanillic acid by 16.5% and 3-methoxytyramine by 66%. The postnatal MPTP was more potent in the prenatal MPTP-exposed offspring. MPTP at 10, 20 and 30 mg/kg, dose-relatedly, reduced striatal TH by 9.4%, 48.6% and 82.4% in the prenatal-phosphate buffered saline (PBS) mice and by 48%, 78.7% and 92.7% in the prenatal-MPTP groups. More importantly, postnatal MPTP at 10 mg/kg that showed slight effects on DA, DOPAC, HVA and 3-MT in the prenatal-PBS offspring, showed 69.9%, 80.0%, 48.4% and 65.4% reductions in the prenatal-MPTP mice. The study may identify a new model for PD, and the outcome suggests that some cases of idiopathic PD may have a fetal basis in which early subtle nigrostriatal impairments occurred and PD symptoms are precipitated later by deteriorating changes in the nigrostriatum, that would not caused symptoms in individuals with normal nigrostriatal system.
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PMID:Modeling a sensitization stage and a precipitation stage for Parkinson's disease using prenatal and postnatal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. 2054 Sep 93


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