Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P50583 (asymmetrical)
 12,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In healthy subjects, 2 EMG responses of the thenar muscles can be distinguished, elicited by electrical stimulation of the median nerve during an isometric contraction: an early spinal response (M1) and a long latency response (LLR) (M2); earlier studies have shown that in patients with Huntington's chorea (HC) this late EMG response is missing. LLR were studied in the nine subjects at risk out of three families with definite HC. In 6 of them, LLR was clearly asymmetrical or absent on one or both sides, while normal LLRs were seen in the rest of the subjects studied; LLR abnormalities found in clinically free members of HC families may assist in early diagnosis of individuals who may later develop symptoms and may help in genetic counselling.
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PMID:Long latency EMG responses in early diagnosis of Huntington's chorea. 183 81

The neuronal dopamine transporter/uptake site can be covalently labeled with the photoaffinity probe 1-(2-[bis-(4-fluorophenyl) methoxy]ethyl)-4-[2-(4-azido-3-[125I]iodophenyl)ethyl]piperazine [( 125I]FAPP) and visualized following sodium dodecyl sulfate polyacrylamide gel electrophoresis and autoradiography. Upon photolysis, [125I]FAPP specifically incorporated into a polypeptide of apparent Mr = 62,000 in membranes from both the putamen and the caudate nucleus of control, Alzheimer's, schizophrenia, and Huntington's diseased brain, and following complete deglycosylation, migrated as an Mr approximately 48,000 polypeptide. In parkinsonian postmortem putamen, however, there was no detectable photoincorporation of [125I]FAPP into the ligand binding subunit of the dopamine transporter. [125I]FAPP did specifically label the Mr 62,000 polypeptide of parkinsonian caudate, although with efficiencies of 20-50% of control. The asymmetrical loss of the dopamine transporter in Parkinson's diseased striatum was confirmed in reversible receptor binding experiments using [3H]GBR-12935 (3H-labeled 1-[2-(diphenylmethoxy) ethyl]-4-(3-phenylpropyl)piperazine). In parkinsonian putamen, mazindol competitively inhibited the binding of [3H]GBR-12935 with an estimated affinity (Ki approximately 2,000 nM) 10 times lower than in controls (Ki approximately 30 nM), while the affinity of maxindol for [3H]GBR-12935 binding in the caudate was equal to that seen with controls (Ki approximately 50 nM). The proportion of [3H]GBR-12935 binding sites recognized by mazindol with high affinity in Parkinson's diseased caudate was, however, reduced by 50-80%.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The dopamine transporter is absent in parkinsonian putamen and reduced in the caudate nucleus. 198 18

Severe degeneration of basal ganglia neurons, particularly the intrinsic neurons of the striatum, is the major underlying neuropathology implicated in clinical attributes of Huntington's disease (HD). The excitotoxin-lesioned striatum provides a useful model for evaluating behavioral parameters of HD. Animals with unilateral excitotoxic lesions exhibit asymmetrical rotational behavior in response to dopamine agonists, such as apomorphine. However, the observed behavior is a pharmacological reaction, and subject to sensitization effects. A behavioral test using undrugged animals may demonstrate a more natural response of the animals to the lesion effects. Recently, we have developed the 'drug-free' elevated body swing test (EBST), and demonstrated that hemiparkinsonian rats exhibited significant biased swing activity. In the present study, we observed that animals with unilateral intrastriatal 3-nitropropionic acid or quinolinic acid lesions displayed a significant biased swing activity with the direction ipsilateral to the lesioned side of the brain. This ipsilateral swing corresponded to the ipsilateral rotational behavior exhibited by the lesioned animals when challenged with apomorphine. The present results demonstrated that the EBST is a sensitive measure for characterizing asymmetrical behavior in animals with striatal lesions.
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PMID:Asymmetrical motor behavior in rats with unilateral striatal excitotoxic lesions as revealed by the elevated body swing test. 779 75

Evidence for genetic anticipation has recently become an important subject of research in clinical psychiatric genetics. Renewed interest in anticipation was evoked by molecular genetic findings of a novel type of mutation termed "unstable DNA." The unstable DNA model can be construed as the "best fit" for schizophrenia twin and family epidemiological data. We have performed a large-scale Southern blot hybridization, asymmetrical PCR-based, and repeat expansion-detection screening for (CAG)n/(CTG)n and (CCG)n/(CGG)n expansions in eastern Canadian schizophrenia multiplex families demonstrating genetic anticipation. There were no differences in (CAG)n/(CTG)n and (CCG)n/(CGG)n pattern distribution either between affected and unaffected individuals or across generations. Our findings do not support the hypothesis that large (CAG)n/(CTG)n or (CCG)n/(CGG)n expansions are the major etiologic factor in schizophrenia. A separate set of experiments directed to the analysis of small (30-130 trinucleotides), Huntington disease-type expansions in individual genes is required in order to fully exclude the presence of (CAG)n/(CTG)n- or (CCG)n/(CGG)n-type unstable mutation.
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PMID:Search for unstable DNA in schizophrenia families with evidence for genetic anticipation. 880 7

Glutamate released in the basal ganglia is involved in the expression of clinical symptoms of neurodegenerative diseases like Parkinson's or Huntington's. Neostriatal neurons are the targets of glutamatergic inputs derived from the cortex and the thalamus acting via AMPA-type as well as other glutamate receptors. To determine the location of subunits of the AMPA subclass of glutamate receptors (GluR) in the rat neostriatum, we applied multiple immunocytochemical techniques using anti-peptide antibodies against the GluR1, GluR2/3, and GluR4 subunits at both the light and electron microscopic levels. All medium spiny efferent neurons, some of which were identified as striatonigral neurons, displayed immunoreactivity for GluR1 and GluR2/3 subunits. Double immunofluorescence revealed that at least 70-90% of parvalbumin-immunopositive GABAergic interneurons were immunoreactive for each of GluR1, GluR2/3, or GluR4 subunits and that at least 40% of choline acetyltransferase-immunopositive cholinergic interneurons were immunopositive for GluR1 or GluR4 subunits. The majority of nitric oxide synthase-immunopositive neurons had no detectable immunoreactivity for any of the AMPA receptor subunits. Electron microscopic analysis confirmed the presence of immunoreactivity for GluR1 and GluR2/3 in the perikarya of spiny neurons and interneurons and GluR4 in perikarya of interneurons only. GluR1 and GluR2/3 subunits were detected in dendrites and spines. A significant population of extrasynaptic receptors was revealed by pre-embedding immunogold labeling along the plasma membranes of perikarya, dendrites, and spines. Receptors were concentrated in the postsynaptic membrane specialization of asymmetrical synapses, as revealed by the postembedding immunogold method. Quantitative analysis demonstrated that immunoreactivity for the GluR1 and GluR2/3 subunits is higher at the periphery than at the middle of the postsynaptic membrane specialization. Our results demonstrate that AMPA receptor subunits are distributed widely and heterogeneously among striatal neurons and are concentrated on the postsynaptic membrane of asymmetrical synaptic specializations, although extrasynaptic receptors are also present.
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PMID:Cellular, subcellular, and subsynaptic distribution of AMPA-type glutamate receptor subunits in the neostriatum of the rat. 898 3

The present study determined the effects of intraventricularly administered glial cell line-derived neurotrophic factor on the behavioral and neurochemical sequelae of unilateral excitotoxic lesions of the striatum. Distinct asymmetrical rotational behavior in response to peripheral administration of amphetamine (5 mg/kg) was noted one and two weeks following injections of quinolinic acid (200 nmol) into two sites in the left striatum. In rats given a single intraventricular injection of glial cell line-derived neurotrophic factor (10-1000 micrograms) 30 min before the toxin, amphetamine-induced rotational behavior was significantly attenuated. Analysis of Nissl-stained coronal sections showed marked neuronal loss in the striatum ipsilateral to the quinolinic acid injections, which was at least partially prevented by glial cell line-derived neurotrophic factor D1 and D2 dopamine binding sites in the striatum, the majority of which are localized to subpopulations of GABAergic neurons, were decreased to a similar extent by quinolinic acid. Moreover, the reduction was attenuated by glial cell line-derived neurotrophic factor treatment to a similar degree, suggesting that the two subpopulations of GABAergic striatal output neurons are equally vulnerable to excitotoxic damage. Concomitant changes in neurotransmitter function as a result of the lesion were also observed: [3H]GABA uptake into striatal target tissues (globus pallidus and substantia nigra) was considerably reduced in the lesioned compared to the contralateral unlesioned tissues, as were [3H]choline and [3H]dopamine uptake into striatal synaptosomes. Similarly, striatal choline acetyltransferase activity was decreased by the lesion. Decrements in neuropeptide levels of similar magnitude were evident ipsilateral to the lesion; substance P, met-enkephalin and dynorphin A contents in the globus pallidus and substantia nigra were significantly reduced. Striatal somatostatin and neuropeptide Y levels were not altered. All of the neurochemical deficits induced by striatal quinolinic acid lesions were attenuated by intraventricular delivery of glial cell line-derived neurotrophic factor. Continuous intraventricular infusion of this trophic factor (10 micrograms/day) over a two-week period did not afford notable improvement compared to the single injection of 10 micrograms. In contrast, continuous infusion of brain-derived neurotrophic factor (10 micrograms/day) directly into the striatum did not affect any of the neurochemical parameters studied. However, neurotrophin-3 (10 micrograms/day) delivery into the striatum significantly increased [3H]GABA uptake, but only modestly affected [3H]choline uptake. The results indicate that glial cell line-derived neurotrophic factor counteracts neuronal damage induced by a striatal excitotoxic insult and support its potential use as a treatment for central nervous system disorders that may be a consequence of excitotoxic processes, such as Huntington's disease.
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PMID:Glial cell line-derived neurotrophic factor attenuates the excitotoxin-induced behavioral and neurochemical deficits in a rodent model of Huntington's disease. 933 Mar 71

The aim of the study was to investigate grip-load force regulation in Huntington's disease (HD) patients as compared to control subjects during the performance of a manipulative task that required rhythmical unimanual or bimanual isodirectional/non-isodirectional actions in the sagittal plane. Results showed that the profile of grip-load ratio force was characterized by maxima and minima that were attained at upward and downward hand positions, respectively. Minimum force ratio was higher in patients than in controls, which points to an elevated baseline that may be related to the inherent bradykinesia observed in HD. Maximum force ratio was also increased in patients, but this effect depended on the performance condition, with largest amplifications occurring during non-isodirectional movements. The latter rescaling may be associated with the complexity of the coordination mode and its asymmetrical load characteristics. In addition, the temporal delay between the grip and load force peaks was augmented in patients versus controls, indicating a disturbed coupled activation of both forces. Furthermore, the interval was largest during non-isodirectional movements followed by isodirectional and unimanual movements, which denotes that the grip-load force coupling deteriorated as a function of coordinative complexity. Together, these data indicate a deficit in the grip-load force constraint due to HD and illustrate the degrading effect of striatal dysfunction on (bi)manual manipulative function.
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PMID:Control of manipulative forces during unimanual and bimanual tasks in patients with Huntington's disease. 1188 10

The inhibitory amino acid, gamma-aminobutyric acid (GABA), plays a critical role in the substantia nigra (SN) in health and disease. GABA transmission is controlled in part by the type(s) of GABA receptor expressed, their subunit composition and their location in relation to GABA release sites. In order to define the subcellular localization of GABA(A) receptors in the SN in normal and pathological conditions, sections of SN from control rats and rats that had received quinolinic acid lesions of the striatum were immunolabelled using the postembedding immunogold technique with antibodies against subunits of the GABA(A) receptor. Immunolabelling for alpha1, beta2/3 and gamma2 subunits was primarily located at symmetrical synapses. Double-labelling revealed that beta2/3 subunit-positive synapses were formed by terminals that were enriched in GABA. Colocalization of alpha1, beta2/3 and gamma2 subunits occurred at individual symmetrical synapses, some of which were identified as degenerating terminals derived from the striatum. In the SN ipsilateral to the striatal lesion there was a significant elevation of immunolabelling for beta2/3 subunits of the GABA(A) receptor at symmetrical synapses, but not of GluR2/3 subunits of the AMPA receptor at asymmetrical synapses. It was concluded that fast GABA(A)-mediated transmission occurs primarily at symmetrical synapses within the SN, that different receptor subunits coexist at individual synapses and that the upregulation of GABA(A) receptors following striatal lesions is expressed as increased receptor density at synapses. The upregulation of GABA(A) receptors in Huntington's disease and its models is thus likely to lead to an increased efficiency of transmission at intact GABAergic synapses in the SN and may partly underlie the motor abnormalities of this disorder.
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PMID:Synaptic localization of GABA(A) receptor subunits in the substantia nigra of the rat: effects of quinolinic acid lesions of the striatum. 1209 2

A variety of immortalized cell lines have been proposed to exhibit sufficient phenotypic plasticity to allow them to replace primary embryonic neurons for restorative cell transplantation. In the present experiments we evaluate the functional viability of one particular cell line, the hNT cells developed by Layton Bioscience, to replace lost neurons and alleviate asymmetrical motor deficits in a unilateral excitotoxic lesion model of Huntington's disease. Because the grafts involved implantation of human-derived cells into a rat host environment, all animals were immunosuppressed. Cyclosporin A and FK-506 were similar in providing effective immunoprotection of the hNT xenografts, and whereas the lesions induced a marked inflammatory response in the host brain, this was not exacerbated by the presence of xenograft cells. The presence of grafted cells was determined with the human-specific antigen HuNu, and good graft survival was demonstrated in almost all animals up to the longest survival examined, 16 weeks posttransplantation. Although the cells exhibited progressively greater maturation and differentiation at 10-day, 4- and 16-week time points, staining for the mature neuronal marker NeuN was at best very weak, and we were unable to detect unequivocal staining with any markers of mature striatal phenotype, including DARPP-32, calbindin, parvalbumin, choline acetyl transferase, or NADPH diaphorase (with in all cases positive control provided by good staining on the intact contralateral side of the brain). Nor were we able to detect any differences between rats with lesions alone and rats with grafts in the contralateral motor deficits exhibited in a test of skilled paw reaching or cylinder placing. These results suggest that further and more extensive studies should be undertaken to assess whether hNT neurons can show more extensive and appropriate maturation and be associated with recovery in appropriate behavioral models, before they may be considered a suitable replacement for primary embryonic cells for clinical application in Huntington's disease.
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PMID:Transplanted hNT cells ("LBS neurons") in a rat model of huntington's disease: good survival, incomplete differentiation, and limited functional recovery. 1512 58

We report on a 28-year-old man who presented with right hand tremor, bradykinesia, and rigidity of his right side extremities. Our case report emphasizes that markedly asymmetrical parkinsonism can be an initial presentation of adult-onset Huntington's disease (HD), and different clinical presentations can be observed in members of an individual HD family with the same CAG repeat length.
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PMID:Markedly asymmetrical parkinsonism as a leading feature of adult-onset Huntington's disease. 1525 54


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