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)

Mice that are homozygous with respect to a mutation (ax(J)) in the ataxia (ax) gene develop severe tremors by 2-3 weeks of age followed by hindlimb paralysis and death by 6-10 weeks of age. Here we show that ax encodes ubiquitin-specific protease 14 (Usp14). Ubiquitin proteases are a large family of cysteine proteases that specifically cleave ubiquitin conjugates. Although Usp14 can cleave a ubiquitin-tagged protein in vitro, it is unable to process polyubiquitin, which is believed to be associated with the protein aggregates seen in Parkinson disease, spinocerebellar ataxia type 1 (SCA1; ref. 4) and gracile axonal dystrophy (GAD). The physiological substrate of Usp14 may therefore contain a mono-ubiquitin side chain, the removal of which would regulate processes such as protein localization and protein activity. Expression of Usp14 is significantly altered in ax(J)/ax(J) mice as a result of the insertion of an intracisternal-A particle (IAP) into intron 5 of Usp14. In contrast to other neurodegenerative disorders such as Parkinson disease and SCA1 in humans and GAD in mice, neither ubiquitin-positive protein aggregates nor neuronal cell loss is detectable in the central nervous system (CNS) of ax(J) mice. Instead, ax(J) mice have defects in synaptic transmission in both the central and peripheral nervous systems. These results suggest that ubiquitin proteases are important in regulating synaptic activity in mammals.
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PMID:Synaptic defects in ataxia mice result from a mutation in Usp14, encoding a ubiquitin-specific protease. 1236 14

The Department of Neurology, Hokkaido University, has been established since 1987, however the bases for neurology had been cultivated through psychiatry and neurosurgery in Hokkaido, especially under the pioneering work by Professor Mitsuo Tsuru. Hokkaido, the northernmost island of Japan, is located between 42 and 46 degrees, and the people have ancestors from various parts of Japan, since this island was reclaimed about 130 years ago. Three major neurological disorders, such as multiple sclerosis(MS), spinocerebellar degeneration(SCD) and Parkinson disease (PD), were discussed on the bases of Hokkaido island. We proved the existence of definite north-south gradient of MS, prevalence rate of 8.6 in Tokachi, Hokkaido, compared with 1-2 in the southern island. SCD, especially hereditary SCD, such as SCA1, SCA2 and SCA14 were reported from Hokkaido. The epidemiological studies of PD showed the prevalence rate of 104.6 at Iwamizawa, Hokkaido in 2000, and we proposed the prevalence rate of PD was close to those of Western countries under the collaborative works with Yonago, Kyoto, and Kagoshima by 2001. Neurology, and its specialization and training programs were also discussed to propose the importance of Neurology in Japan.
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PMID:["Time, place and person" and neurology]. 1278 63

DNA tests in normal subjects and patients with ataxia and Parkinson's disease (PD) were carried out to assess the frequency of spinocerebellar ataxia (SCA) and to document the distribution of SCA mutations underlying ethnic Chinese in Taiwan. MJD/SCA3 (46%) was the most common autosomal dominant SCA in the Taiwanese cohort, followed by SCA6 (18%) and SCA1 (3%). No expansions of SCA types 2, 10, 12, or dentatorubropallidoluysian atrophy (DRPLA) were detected. The clinical phenotypes of these affected SCA patients were very heterogeneous. All of them showed clinical symptoms of cerebellar ataxia, with or without other associated features. The frequencies of large normal alleles are closely associated with the prevalence of SCA1, SCA2, MJD/SCA3, SCA6, and DRPLA among Taiwanese, Japanese, and Caucasians. Interestingly, abnormal expansions of SCA8 and SCA17 genes were detected in patients with PD. The clinical presentation for these patients is typical of idiopathic PD with the following characteristics: late onset of disease, resting tremor in the limbs, rigidity, bradykinesia, and a good response to levodopa. This study appears to be the first report describing the PD phenotype in association with an expanded allele in the TATA-binding protein gene and suggests that SCA8 may also be a cause of typical PD.
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PMID:Genetic testing in spinocerebellar ataxia in Taiwan: expansions of trinucleotide repeats in SCA8 and SCA17 are associated with typical Parkinson's disease. 1475 71

In 1997 a mutation in the a-synuclein (SNCA) gene was associated with familial autosomal dominant Parkinson's disease (PD). Since then, several loci (PARK1-15) and genes have been linked to familial forms of the disease. There is now sufficient evidence that six of the so far identified genes at PARK loci (a-synuclein, leucine-rich repeat kinase 2, parkin, PTEN-induced putative kinase 1, DJ-1, and ATP13A2) cause inherited forms of typical PD or parkinsonian syndromes. Other genes at non-PARK loci (MAPT, SCA1, SCA2, spatacsin, POLG1) cause syndromes with parkinsonism as one of the symptoms. The majority of PD cases are however sporadic "idiopathic" forms, and the recent application of genome-wide screening revealed almost 20 genes that might contribute to disease risk. In addition, increasing evidence suggests that epigenetic mechanisms, such as DNA methylation, histone modifications, and small RNA-mediated mechanisms, could regulate the expression of PD-related genes.
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PMID:Genetics and epigenetics of Parkinson's disease. 2262

This study was conducted to find out Spinocerebellar Ataxias (SCA) by genetic analysis from those patients presenting with Parkinsonism in the Neurology department of Mymensingh Medical College Hospital, Bangladesh. A sample of about 5ml blood was collected by venipuncture in EDTA tube after having informed consent from each patients and healthy individual, with due Institutional Ethical committee approval for genetic study of 7 healthy people and 9 patients. The neurological disorder along with a complete physical and/or psychological, as well as family history and demographic data was recorded with a prescribed questionnaire by the neurologists of Mymensingh Medical College Hospital. Extraction of genomic DNA from the venous blood using Flexi Gene DNA kit (Qiagen, Japan) was performed in Faculty of Veterinary Science, Bangladesh Agricultural University, Mymensingh, Bangladesh. The extracted DNA was stored, accumulated and then were sent to Division of Clinical Genetics, Department of Medical Genetics, Osaka University Medical School, Suita, Osaka 565 0871, Japan for PCR and further analysis. PCR amplification of the CAG repeat was performed for the SCA1, SCA2, SCA3, SCA6 loci using primers SCA1N-F1 and SCA1N-R1, SCA2-F1 and SCA2-R1, MJDF1 and MJDR1, SCA6-F1 and SCA6-R1, respectively. SCA1 PCR of both healthy individual and suspected Parkinsons Disease (PD) patients DNA was found 250 bp (no. of CAG repeats=36). SCA2 PCR products reveal the DNA products of about 150 bp (no. of CAG repeats=23) except one patient that was suspected and it was sequenced and revealed 175bp (no. of CAG repeats=30). SCA3 PCR product size of both healthy individual and patient DNA was within 250 (no. of CAG repeats=11) to 300 bp (no. of CAG repeats=28) except one patient which was about 320 bp and its CAG repeats was about 34. SCA6 PCR product size of both healthy individual and patient DNA was about 150 bp (no. of CAG repeats=16).
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PMID:Genetic testing for spinocerebellar ataxias in patients diagnosed as Parkinson's disease in Bangladesh. 2572 67

Protein aggregates are hallmarks of nearly all age-related neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and several polyglutamine diseases such as Huntington's disease and different forms of spinocerebellar ataxias (SCA; SCA1-3, SCA6, and SCA7). The collapse of cellular protein homoeostasis can be both a cause and a consequence of this protein aggregation. Boosting components of the cellular protein quality control system has been widely investigated as a strategy to counteract protein aggregates or their toxic consequences. Heat shock proteins (HSPs) play a central part in regulating protein quality control and contribute to protein aggregation and disaggregation. Therefore, HSPs are viable targets for the development of drugs aimed at reducing pathogenic protein aggregates that are thought to contribute to the development of so many neurodegenerative disorders.
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PMID:Heat shock proteins as potential targets for protective strategies in neurodegeneration. 2710 72

Spinocerebellar ataxia (SCA) types 1, 2, 3, 6, and 7, associated with a (CAG)n repeat expansion in coding sequences, are the most prevalent autosomal dominant ataxias worldwide (approximately 60% of the cases). In addition, the phenotype of SCA2 expansions has been now extended to Parkinson disease and amyotrophic lateral sclerosis. Their diagnosis is currently based on a PCR to identify small expanded alleles, followed by a second-level test whenever a false normal homozygous or a CAT interruption in SCA1 needs to be verified. Next-generation sequencing still does not allow efficient detection of these repeats. Here, we show the efficacy of a novel, rapid, and cost-effective method to identify and size pathogenic expansions in SCA1, 2, 3, 6, and 7 and recognize large alleles or interruptions without a second-level test. Twenty-five healthy controls and 33 expansion carriers were analyzed: alleles migrated consistently in different PCRs and capillary runs, and homozygous individuals were always distinguishable from heterozygous carriers of both common and large (>100 repeats) pathogenic CAG expansions. Repeat number could be calculated counting the number of peaks, except for the largest SCA2 and SCA7 alleles. Interruptions in SCA1 were always visible. Overall, our method allows a simpler, cost-effective, and sensibly faster SCA diagnostic protocol compared with the standard technique and to the still unadapted next-generation sequencing.
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PMID:Spinocerebellar Ataxia Tethering PCR: A Rapid Genetic Test for the Diagnosis of Spinocerebellar Ataxia Types 1, 2, 3, 6, and 7 by PCR and Capillary Electrophoresis. 2946 66

The underlying biology of essential tremor (ET) is poorly understood. Purkinje cell (PC) loss has been observed in some studies, although this finding remains somewhat controversial. Basket cells are interneurons whose axonal collaterals form a plexus around PC soma. When there is PC loss, this basket plexus appears empty. We used dual immunohistochemical staining for calbindin D28k and glutamic acid decarboxylase to quantify "empty baskets" as an indirect and alternative method of detecting PC loss. Microscopic analyses on 127 brains included ET and a spectrum of motor neurodegenerative diseases (50 ET, 27 spinocerebellar ataxias [SCAs], 25 Parkinson disease, 25 controls). The median percentage of empty baskets in ET patients was 1.5 times higher than controls (48.8% vs 33.5%, p < 0.001) but lower in ET than in SCA1 (59.7%, p = 0.011), SCA2 (77.5%, p = 0.003), and SCA6 (87.0%, p < 0.001). PC loss is not a feature of SCA3, and the median percentage of empty baskets (30.1%) was similar to controls (p = 0.303). These data provide support for PC loss in ET and are consistent with the notion that ET could represent a mild form of cerebellar degeneration with an intermediate degree of PC loss.
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PMID:A Quantitative Study of Empty Baskets in Essential Tremor and Other Motor Neurodegenerative Diseases. 3059 May 99

Several morphological changes, centered in/around Purkinje cells (PCs), have been identified in the cerebellum of essential tremor (ET) patients. These changes have not been contextualized within a broader degenerative disease spectrum, limiting their interpretability. To address this, we compared the severity and patterning of degenerative changes within the cerebellar cortex in patients with ET, other neurodegenerative disorders of the cerebellum (spinocerebellar ataxias (SCAs), multiple system atrophy (MSA)], and other disorders that may involve the cerebellum [Parkinson's disease (PD), dystonia]. Using a postmortem series of 156 brains [50 ET, 23 SCA (6 SCA3; 17 SCA 1, 2 or 6), 15 MSA, 29 PD, 14 dystonia, 25 controls], we generated data on 37 quantitative morphologic metrics, which were grouped into 8 broad categories: (1) PC loss, (2) heterotopic PCs, (3) PC dendritic changes, (4) PC axonal changes (torpedoes), (5) PC axonal changes (other than torpedoes), (6) PC axonal changes (torpedo-associated), (7) basket cell axonal hypertrophy, (8) climbing fiber-PC synaptic changes. Our analyses used z scored raw data for each metric across all diagnoses (5772 total data items). Principal component analysis revealed that diagnostic groups were not uniform with respect to cerebellar pathology. Dystonia and PD each differed from controls in only 2/37 metrics, whereas ET differed in 21, SCA3 in 8, MSA in 19, and SCA1/2/6 in 26 metrics. Comparing ET with primary disorders of cerebellar degeneration (i.e., SCAs), we observed a spectrum of changes reflecting differences of degree, being generally mild in ET and SCA3 and more severe in SCA1/2/6. Comparative analyses across morphologic categories demonstrated differences in relative expression, defining distinctive patterns of changes in these groups. Thus, the degree of cerebellar degeneration in ET aligns it with a milder end in the spectrum of cerebellar degenerative disorders, and a somewhat distinctive signature of degenerative changes marks each of these disorders.
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PMID:Contextualizing the pathology in the essential tremor cerebellar cortex: a patholog-omics approach. 3131 29