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)

Many lines of evidence implicate mitochondria in phenotypic variation: (a) rare mutations in mitochondrial proteins cause metabolic, neurological, and muscular disorders; (b) alterations in oxidative phosphorylation are characteristic of type 2 diabetes, Parkinson disease, Huntington disease, and other diseases; and (c) common missense variants in the mitochondrial genome (mtDNA) have been implicated as having been subject to natural selection for adaptation to cold climates and contributing to "energy deficiency" diseases today. To test the hypothesis that common mtDNA variation influences human physiology and disease, we identified all 144 variants with frequency >1% in Europeans from >900 publicly available European mtDNA sequences and selected 64 tagging single-nucleotide polymorphisms that efficiently capture all common variation (except the hypervariable D-loop). Next, we evaluated the complete set of common mtDNA variants for association with type 2 diabetes in a sample of 3,304 diabetics and 3,304 matched nondiabetic individuals. Association of mtDNA variants with other metabolic traits (body mass index, measures of insulin secretion and action, blood pressure, and cholesterol) was also tested in subsets of this sample. We did not find a significant association of common mtDNA variants with these metabolic phenotypes. Moreover, we failed to identify any physiological effect of alleles that were previously proposed to have been adaptive for energy metabolism in human evolution. More generally, this comprehensive association-testing framework can readily be applied to other diseases for which mitochondrial dysfunction has been implicated.
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PMID:Comprehensive association testing of common mitochondrial DNA variation in metabolic disease. 1730 9

Homocysteine levels are affected by diet factors such as vitamin deficiencies, non-diet factors such as genetic disorders, and stress exposure. Hyperhomocysteinemia has been implicated in several disorders, including cardiovascular disease, depression, schizophrenia, Alzheimer's and Parkinson's disease. Since sex differences play a role both in stress responses and in susceptibility to various diseases, the objective of this study was to evaluate possible alterations in homocysteine metabolism including cysteine, folate, and vitamin B(6), and oxidative stress markers in female rats exposed to different types of acute stress. Female rats were randomly distributed into eight groups according to stress manipulation (restraint, swimming, cold and control) and estrous cycle (diestrus and estrus). In general no significant differences were seen between rats in estrus and diestrus. Restraint stress was the only type of stress that altered homocysteine concentrations (+33% relative to controls). An increase in levels of thiobarbituric acid reactive substances (TBARS) and a decrease in total glutathione (GSHt) concentration were also observed in animals subjected to restraint and swimming stress, suggesting the possibility of oxidative damage. Thus, both the homocysteine results and the oxidative stress data indicated that restraint stress was the most powerful stress manipulation in female rats, as previously observed in male rats. These findings indicate that hormonal and gonadal differences do not interfere with stress responses related to homocysteine metabolism and suggest that putative gender-related differences in homocysteine responses are probably not involved in the differential prevalence of some diseases in human males and females.
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PMID:Acute stressor-selective effects on homocysteine metabolism and oxidative stress parameters in female rats. 1705 2

Leucine-Rich Repeat Kinase 2 (LRRK2) is a causative gene for the autosomal dominant form of Parkinson's disease (PD). The gene encodes the approximately 280 kDa LRRK2 protein composed of domains such as leucine-rich repeats, Ras in complex proteins (Roc) followed by C-terminal of Roc (COR), mitogen-activated protein kinase kinase kinase (MAPKKK) and WD40. However, the normal function of the protein as well as its contribution to the pathogenesis of PD remains largely unknown. Here we describe the localization of LRRK2 in Golgi apparatus, plasma membrane and synaptic vesicles in cultured cells including mouse primary neurons. The membrane association of LRRK2 resists solubilization by ice-cold 1% Triton X-100, indicating its association through lipid rafts. To investigate whether mutations found in PD patients affect the localization of LRRK2, we transfected various LRRK2 mutants into cultured cells and performed fractionation experiments. Unexpectedly, the mutants are collected in both membrane and soluble fractions in a manner similar to wild type (WT). I2020T mutant LRRK2 associates with lipid rafts, similar to the WT. The lipid raft association of LRRK2 mutants as well as WT LRRK2 suggests that alteration of LRRK2 function on lipid rafts contributes to the pathogenesis of PD.
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PMID:Leucine-rich repeat kinase 2 associates with lipid rafts. 1734 85

Transcranial direct current stimulation (tDCS) and caloric vestibular stimulation (CVS) are safe methods for selectively modulating cortical excitability and activation, respectively, which have recently received increased interest regarding possible clinical applications. tDCS involves the application of low currents to the scalp via cathodal and anodal electrodes and has been shown to affect a range of motor, somatosensory, visual, affective and cognitive functions. Therapeutic effects have been demonstrated in clinical trials of tDCS for a variety of conditions including tinnitus, post-stroke motor deficits, fibromyalgia, depression, epilepsy and Parkinson's disease. Its effects can be modulated by combination with pharmacological treatment and it may influence the efficacy of other neurostimulatory techniques such as transcranial magnetic stimulation. CVS involves irrigating the auditory canal with cold water which induces a temperature gradient across the semicircular canals of the vestibular apparatus. This has been shown in functional brain-imaging studies to result in activation in several contralateral cortical and subcortical brain regions. CVS has also been shown to have effects on a wide range of visual and cognitive phenomena, as well as on post-stroke conditions, mania and chronic pain states. Both these techniques have been shown to modulate a range of brain functions, and display potential as clinical treatments. Importantly, they are both inexpensive relative to other brain stimulation techniques such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS).
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PMID:The use of tDCS and CVS as methods of non-invasive brain stimulation. 1790 Jul 3

Abnormal folding and accumulation of alpha-synuclein is implicated in several neurological disorders including Parkinson's disease. Although alpha-synuclein is a typical cytoplasmic protein, a small amount of both monomeric and aggregated forms is secreted from cells and is present in human body fluids, such as cerebrospinal fluid. Extracellular alpha-synuclein aggregates have been shown to be neurotoxic, posing a challenge to any cell exposed to them. Here, we examine the internalization of various forms of extracellular alpha-synuclein, including fibrils, oligomers, and monomer, into neuronal cells and their subsequent degradation. Internalization of fibrillar alpha-synuclein could be inhibited by low temperature or the expression of a dominant-negative mutant dynamin-1 K44A, suggesting the endocytosis-mediated internalization. The internalized fibrils moved through the endosomal pathway and were degraded in the lysosome, which ultimately resulted in the clearance of the alpha-synuclein aggregates from the culture medium. Non-fibrillar oligomeric aggregates were also internalized via endocytosis and degraded by the lysosome. In contrast to aggregate uptake, the internalization of monomeric alpha-synuclein was unaffected by cold temperature and the expression of dynamin-1 K44A, consistent with direct translocation across the plasma membrane. Internalized monomers rapidly pass the plasma membrane, escaping the cells before being degraded by the cellular proteolytic systems. These results suggest that only aggregated forms of extracellular alpha-synuclein can be cleared by cell-mediated uptake and degradation, and this might represent a mechanism of preventing neurons from exposure to potentially toxic alpha-synuclein.
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PMID:Assembly-dependent endocytosis and clearance of extracellular alpha-synuclein. 1829 4

Sensory disturbances are part of the clinical picture of Parkinson's disease. Abnormalities in sensory processing, through a basal ganglia involvement, are thought to be responsible for the sensory dysfunction since sensory nerve conduction velocity (NCV) is usually normal. However, NCV does not examine small fibres or terminal endings of large sensory fibres, whereas skin biopsy is more suitable for these purposes. To evaluate peripheral sensory nerves in Parkinson's disease, we studied cutaneous free and encapsulated sensory nerve endings in 18 patients and 30 healthy controls using 3-mm punch biopsies from glabrous and hairy skin. Ten patients had additional skin biopsies from the contralateral side. Further evaluation included NCV and Quantitative Sensory Testing. Parkinson's disease patients showed a significant increase in tactile and thermal thresholds (P < 0.01), a significant reduction in mechanical pain perception (P < 0.01) and significant loss of epidermal nerve fibres (ENFs) and Meissner corpuscles (MCs) (P < 0.01). In patients with bilateral biopsies, loss of pain perception and ENFs was higher on the more affected side (P < 0.01). We found evidence suggesting attempts at counteracting degenerative processes as increased branching, sprouting of nerves and enlargement of the vascular bed. Morphological and functional findings did not correlate with age or disease duration. Disease severity correlated with loss of MCs and reduction in cold perception and pain perception. We demonstrated a peripheral deafferentation in Parkinson's disease that could play a major role in the pathogenesis of the sensory dysfunction.
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PMID:Sensory deficit in Parkinson's disease: evidence of a cutaneous denervation. 1851 69

One of the clinical features in the patients with Parkinson's disease (PD) is an apparent low incidence of colds. MxA protein is an interferon-induced protein which inhibits influenza A viral infection. MxA protein has been found in association with Lewy bodies in neurons in PD patients' brains. We performed a semiquantitative mRNA analysis by reverse transcription-polymerase chain reaction using specific primers for MxA protein. When the peripheral blood mononuclear cells (PBMC) were incubated with alpha-interferon (alpha-IFN), the relative levels of mRNA from the PD patients increased equally to those of the normal controls. However, when PBMC were incubated without alpha-IFN, the relative levels of mRNA in the PBMC from PD patients showed marked lower levels overall compared with those of the normal controls. These results may mean that the induction of MxA mRNA by alpha-IFN in the PD patients is higher than in the controls and suggest that a remarkable increase of MxA mRNA may be linked to the clinical tendency to rarely catch a cold among the PD patients.
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PMID:Expression of MxA mRNA in peripheral blood mononuclear cells in Parkinson's disease. 1859 Nov 18

Plastic changes within the striatum resulting from pulsatile dopaminergic stimulation are thought to lead to dyskinesia in patients with Parkinson's disease (PD). The basal ganglia play a role in processing pain. We hypothesized that the plastic changes that lead to dyskinesia may also mediate pain responses. Our objective was to compare the change in pain sensitivity after levodopa administration between stable responders, fluctuators without dyskinesia, and dyskinetic patients, and to compare pain sensitivity between PD and healthy subjects. Fifty patients with PD were assessed with cold water immersion after overnight withdrawal of dopaminergic medications and again after a standard levodopa challenge, and carefully classified into stable responder (n = 12), fluctuator (n = 15), and dyskinetic (n = 23) groups. Twenty age-matched controls were also tested. PD patients "off"-medication had a lower threshold (P = 0.016) and tolerance (P < 0.0001) to cold pain compared to controls. After levodopa administration, dyskinetic patients experienced a large increase in cold pain threshold (48%) and tolerance (66%) that was absent in stable responders (P = 0.038 and P = 0.015); there was no significant difference in pain sensitivity change scores between the fluctuator and either the stable responder or dyskinetic groups. Our results suggest that dyskinesia and pain may share common pathophysiological mechanisms in PD.
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PMID:Do dyskinesia and pain share common pathophysiological mechanisms in Parkinson's disease? 1993 58

The cold hand sign (CHS) is a distinct feature of multiple system atrophy (MSA), but its pathophysiology is poorly understood. We, therefore, conducted a study to examine the skin temperature and the skin blood flow at rest and after local heating in 6 age-matched MSA patients with CHS (MSA + CHS), 18 MSA patients without CHS (MSA - CHS) and 13 patients with idiopathic Parkinson's disease (PD). Basal skin temperature and blood flow were significantly lower in MSA + CHS patients than in MSA - CHS or PD patients. Local heating induced a greater response in terms of amplitude in MSA + CHS compared to MSA - CHS and PD. Considering kinetics, skin blood flow increment per 1 degrees C was higher in MSA + CHS than MSA - CHS but was similar when compared to PD patients. Skin blood flow rate (change per second) did not differ among the groups. Our findings suggest that despite impaired basal skin perfusion, the skin vasomotor response to local heating is intact in MSA + CHS but disturbed in MSA - CHS. By measuring skin temperature and blood flow, the presence of CHS can be diagnosed in MSA patients. Further studies are necessary to understand regulation of skin perfusion in patients with extrapyramidal disease.
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PMID:The cold hand sign in multiple system atrophy: skin perfusion revisited. 2015 11

Nonviral plasmid DNA is delivered to the brain via a transvascular route across the blood-brain barrier (BBB) following intravenous administration of DNA encapsulated within Trojan horse liposomes (THLs), also called PEGylated immunoliposomes (PILs). The liposome surface is covered with several thousand strands of polymer (e.g., polyethylene glycol [PEG]), and the tips of 1%-2% of the polymer strands are conjugated with a targeting monoclonal antibody that acts as a molecular Trojan horse (MTH). The MTH binds to a receptor (e.g., for transferrin or insulin) on the BBB and brain cell membrane, triggering receptor-mediated transcytosis of the THL across the BBB in vivo, and receptor-mediated endocytosis into brain cells beyond the BBB. The persistence of transgene expression in the brain is inversely related to the rate of degradation of the episomal plasmid DNA. THL technology enables an exogenous gene to be widely expressed in the majority of cells in adult brain (or other organs) within 1 d of a single intravenous administration. Applications of the THLs include tissue-specific gene expression with tissue-specific promoters, complete normalization of striatal tyrosine hydroxylase in experimental Parkinson's disease following intravenous tyrosine hydroxylase gene therapy, a 100% increase in survival time of mice with brain tumors following weekly intravenous antisense gene therapy using THLs, and a 90% increase in survival time with weekly intravenous RNA interference (RNAi) gene therapy in mice with intracranial brain tumors. This protocol describes the preparation of THLs for use in gene transfer in vitro or in vivo.
Cold Spring Harb Protoc 2010 Apr
PMID:Preparation of Trojan horse liposomes (THLs) for gene transfer across the blood-brain barrier. 2036 Mar 61


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