Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0233565 (bradykinesia)
 2,352 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic influences are thought by many to play an important role in the cause of Parkinson's disease. We studied two closely intermarried families (Family G) whose ancestors immigrated to the United States from Russia. We investigated this family clinically, genealogically, and pathologically. Our pedigree contained 102 members spanning six generations, with 10 affected individuals and 1 affected spouse. Detailed telephone interviews were conducted with affected individuals, with their spouses, and with their at-risk siblings. Medical records of deceased and living affected patients were collected. Physical examinations were performed on 7 at-risk and 5 affected persons. Typical levodopa-responsive parkinsonism with bradykinesia, rigidity, resting tremor, and impaired postural reflexes was seen in 4 members, dementia was present in 3, and 3 had both dementia and parkinsonism. An autopsy completed on 1 individual, our index case, demonstrated Lewy bodies in the brainstem and neocortex and ubiquitin-positive neuritic degeneration in the CA2-3 region of the hippocampus, consistent with the limbic (transitional) form of Lewy body disease. This family is distinct both clinically and pathologically from several previously reported parkinsonian kindreds.
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PMID:Familial parkinsonism, dementia, and Lewy body disease: study of family G. 938 76

The frontotemporal dementias are a group of relatively new and evolving clinical and pathologic entities. The predominant frontal-temporal atrophy causes a variety of clinical syndromes, usually dominated by disturbances in behavior, mood, and speech. The motor neuron disease-inclusion dementia (MNDID) subtype is characterized by the accumulation of specific intraneuronal ubiquitin-immunoreactive inclusions with the complete absence of tau immunoreactivity. We present a patient with the clinical and neuroimaging characteristics of a highly asymmetric neurodegenerative condition distinguished by limb rigidity, bradykinesia, dystonia with an alien limb phenomenon, cortical sensory findings, and limb apraxia. His premorbid diagnosis was cortical-basal ganglionic degeneration but he had the typical histologic features of a frontotemporal dementia of the MNDID subtype.
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PMID:Motor neuron disease-inclusion dementia presenting as cortical-basal ganglionic degeneration. 1043 7

In mammalian cells, regulation of the expression of proteins involved in iron metabolism is achieved through interactions of iron-sensing proteins known as iron regulatory proteins (IRPs), with transcripts that contain RNA stem-loop structures referred to as iron responsive elements (IREs). Two distinct but highly homologous proteins, IRP1 and IRP2, bind IREs with high affinity when cells are depleted of iron, inhibiting translation of some transcripts, such as ferritin, or turnover of others, such as the transferrin receptor (TFRC). IRPs sense cytosolic iron levels and modify expression of proteins involved in iron uptake, export and sequestration according to the needs of individual cells. Here we generate mice with a targeted disruption of the gene encoding Irp2 (Ireb2). These mutant mice misregulate iron metabolism in the intestinal mucosa and the central nervous system. In adulthood, Ireb2(-/-) mice develop a movement disorder characterized by ataxia, bradykinesia and tremor. Significant accumulations of iron in white matter tracts and nuclei throughout the brain precede the onset of neurodegeneration and movement disorder symptoms by many months. Ferric iron accumulates in the cytosol of neurons and oligodendrocytes in distinctive regions of the brain. Abnormal accumulations of ferritin colocalize with iron accumulations in populations of neurons that degenerate, and iron-laden oligodendrocytes accumulate ubiquitin-positive inclusions. Thus, misregulation of iron metabolism leads to neurodegenerative disease in Ireb2(-/-) mice and may contribute to the pathogenesis of comparable human neurodegenerative diseases.
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PMID:Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. 1117 92

We have recently identified a novel SCA form in nine patients from four Japanese pedigrees through the screening for expanded polyglutamine tracts by Western blotting analysis with a monoclonal 1 C 2 antibody that recognizes specifically pathological polyglutamine tracts. This disease is caused by an abnormal CAG/CAA expansion in the TATA-binding protein gene (TBP), a general transcription initiation factor. This abnormal expansion of glutamine tracts in TBP ranges 47 to 55 repeats, whereas the normal repeat number ranges from 29 to 42. Immunocytochemical examination of a postmortem brain that carried 48 CAG repeats detected neuronal intranuclear inclusion bodies (NIIs) that stained with anti-ubiquitin antibody, anti-TBP antibody and with the 1 C 2 antibody. Most patients presented in the third decade with gait ataxia and dementia, progressing over several decades to include bradykinesia, dysmetria, dysdiadockokinesis, hyperreflexia and paucity of movement. No abnormal eye movements were present in any patient. This disease resembles the spinocerebellar ataxias including Dentato-rubal pallidoluysian atrophy (DRPLA) more closely than any other form of neurodegenerative disorder. Further study of this disease should provide important information for unraveling the molecular pathogenesis of neuronal cell degeneration as well as for the development of future therapeutic interventions.
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PMID:[SCA17, a novel polyglutamine disease caused by the expansion of polyglutamine tracts in TATA-binding protein]. 1223 15

We report a case displaying upper motor sign, parkinsonism, and behavioral abnormality, with marked degeneration of the precentral cortex, neostriatum and frontotemporal lobes, as well as ubiquitinated neuronal inclusions. The patient was a 66-year-old male at the time of death. At age 57, he noticed progressive difficulties in speaking and swallowing. At age 60, he was severely anarthric and displayed emotional lability and incontinence. Neurologically, very poor movement of tongue was observed, but without atrophy or fasciculation. Deep tendon reflexes were hyperactive. Grasp reflex and snout reflex were also positive. Needle electromyography revealed no abnormalities. A diagnosis of primary lateral sclerosis and character change was made. At age 62, he developed bradykinesia and rigidity of the neck and all extremities. Treatment with carbidopa-levodopa was initiated, but resulted in minimal improvement. At age 65, he was bed-ridden, and had repeated occurrences of aspiration pneumonia; he died of pneumonia. Neuropathological examination revealed marked atrophy of the frontal and temporal lobes with Betz cells completely absent and moderate atrophy of the neostriatum. The spinal cord and nerve roots appeared normal. Immunohistochemically, ubiquitin-positive but tau-negative intraneuronal inclusions were found in the frontal and temporal cortices, including the precentral cortex and the hippocampal dentate gyrus, and the neostriatum. This case could be included with inclusion-associated disorders such as frontotemporal dementia or amyotrophic lateral sclerosis with dementia, and furthermore, predominant upper motor sign and parkinsonism could represent phenotypes of clinical manifestations with such inclusions.
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PMID:Frontotemporal dementia with ubiquitinated neuronal inclusions presenting with primary lateral sclerosis and parkinsonism: clinicopathological report of an autopsy case. 1476 75

Environmental toxins have been implicated in the etiology of Parkinson's disease. Recent findings of defects in the ubiquitin-proteasome system in hereditary and sporadic forms of the illness suggest that environmental proteasome inhibitors are candidate PD-inducing toxins. Here, we systemically injected six doses of naturally occurring (epoxomicin) or synthetic (Z-lle-Glu(OtBu)-Ala-Leu-al [PSI]) proteasome inhibitors into adult rats over a period of 2 weeks. After a latency of 1 to 2 weeks, animals developed progressive parkinsonism with bradykinesia, rigidity, tremor, and an abnormal posture, which improved with apomorphine treatment. Positron emission tomography demonstrated reduced carbon-11-labeled 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT) binding to dopaminergic nerve terminals in the striatum, indicative of degeneration of the nigrostriatal pathway. Postmortem analyses showed striatal dopamine depletion and dopaminergic cell death with apoptosis and inflammation in the substantia nigra pars compacta. In addition, neurodegeneration occurred in the locus coeruleus, dorsal motor nucleus of the vagus, and the nucleus basalis of Meynert. At neurodegenerative sites, intracytoplasmic, eosinophilic, alpha-synuclein/ubiquitin-containing, inclusions resembling Lewy bodies were present in some of the remaining neurons. This animal model induced by proteasome inhibitors closely recapitulates key features of PD and may be valuable in studying etiopathogenic mechanisms and putative neuroprotective therapies for the illness.
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PMID:Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease. 1686 91

Parkinson's disease (PD) is a common neurodegenerative disorder with clinical features of bradykinesia, rigidity and resting tremor resulting from the deficiency of dopamine in the nigrostriatal system. Recently, PARK6 was identified as a novel locus associated with autosomal recessive PD. Here we report the identification and characterization of a novel human deubiquitylating gene (USP31), which maps to the critical PARK6 region. Database analysis and 5' RACE identified a 4070bp cDNA, encoded by 27 exons spanning approximately 105kbp of genomic sequence. The predicted protein of 1035 amino acids included a conserved ubiquitin hydrolase region (Prosite profile PS50235), a DUSP (domain in ubiquitin specific proteases-Smart00695) and a ubiquitin-like domain (Prosite pattern PS00299). Northern blot analysis revealed a single USP31 transcript of approximately 4 kb, which was primarily expressed in the testis and lung.
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PMID:Identification of the human ubiquitin specific protease 31 (USP31) gene: structure, sequence and expression analysis. 1535 49

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by rigidity, bradykinesia, postural instability and resting tremor. The major symptoms are related to the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. The recent discovery of PARK genes causing familial forms of PD has led to a new approach in the study of the disease. The cause and pathogenesis of PD remains unknown; mitochondrial dysfunction, oxidative damage, endoplasmic reticulum stress, failure of the ubiquitin-proteasome system, environmental factors and genetic predisposition might all be involved. Toxin-induced PD animal models and genetic mouse models that mimic familial PD have contributed to investigating the molecular pathogenesis and treatment of the disease. Recently, neurogenesis in the striatum and subventricular zones in PD animal models have been reported. This review discusses molecular pathogenesis, experimental disease models and recent cell-based therapeutic approaches for PD.
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PMID:Molecular pathogenesis, experimental models and new therapeutic strategies for Parkinson's disease. 1763 51

The systemic rotenone model of Parkinson's disease (PD) accurately replicates many aspects of the pathology of human PD and has provided insights into the pathogenesis of PD. The major limitation of the rotenone model has been its variability, both in terms of the percentage of animals that develop a clear-cut nigrostriatal lesion and the extent of that lesion. The goal here was to develop an improved and highly reproducible rotenone model of PD. In these studies, male Lewis rats in three age groups (3, 7 or 12-14 months) were administered rotenone (2.75 or 3.0 mg/kg/day) in a specialized vehicle by daily intraperitoneal injection. All rotenone-treated animals developed bradykinesia, postural instability, and/or rigidity, which were reversed by apomorphine, consistent with a lesion of the nigrostriatal dopamine system. Animals were sacrificed when the PD phenotype became debilitating. Rotenone treatment caused a 45% loss of tyrosine hydroxylase-positive substantia nigra neurons and a commensurate loss of striatal dopamine. Additionally, in rotenone-treated animals, alpha-synuclein and poly-ubiquitin positive aggregates were observed in dopamine neurons of the substantia nigra. In summary, this version of the rotenone model is highly reproducible and may provide an excellent tool to test new neuroprotective strategies.
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PMID:A highly reproducible rotenone model of Parkinson's disease. 1938 59

Parkinson's disease is a neurodegenerative condition characterized by tremor, rigidity, bradykinesia, and postural instability. Smoking is an inverse risk factor for Parkinson's disease, although the mechanism for this apparent neuroprotection is not definitively established. Smoking consistently upregulates nicotinic acetylcholine receptor levels in various brain regions known to be involved in Parkinson's disease. The ubiquitin-proteasome system--the system that tags and removes unwanted, misfolded, or damaged proteins from cells--regulates nicotinic receptor levels. The ubiquitin-proteasome system has also been implicated in Parkinson's disease, with aberrant activity identified in both sporadic and familial forms of the disease. The involvement of the ubiquitin-proteasome system in nicotinic receptor regulation and Parkinson's disease pathology suggests a link between the two, which forms the basis of the present hypothesis. Specifically, this paper considers the hypothesis that smoking reduces the risk of Parkinson's disease through the upregulation of nicotinic cholinergic receptors in key brain regions involved in Parkinson's disease. This receptor upregulation is hypothesized to increase activity of the ubiquitin-proteasome system, which is believed to prevent neurodegeneration caused by the accumulation of misfolded or damaged proteins or other consequences of inadequate protein sequestration and/or degradation. This hypothesis is supported by evidence documenting the upregulation of nicotinic receptors in the brains of smokers, neuroprotective effects of nicotine, reduced activity of the ubiquitin-proteasome in Parkinson's disease, and increased activity of the ubiquitin-proteasome system in animals exposed to chronic nicotine. Additional research is needed to test several predictions of the hypothesis, including increased activity of the ubiquitin-proteasome system in key brain regions of smokers.
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PMID:Does smoking reduce the risk of Parkinson's disease through stimulation of the ubiquitin-proteasome system? 1954 50


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