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)

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

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. It is urgently needed to elucidate the cause of the disease and to establish neuroprotective treatment. We have been working on the etiology and pathogenesis of PD for many years and we found selective loss of mitochondrial complex I and the alpha-ketoglutarate dehydrogenase complex in the nigral neurons of patients with PD. Our observation firmly established mitochondrial defects in PD. Mitochondrial respiratory failure induces oxidative damage in neurons, and we found increase in hydroxynonenal and 8-oxo-deoxyguanine, indices of oxidative damage, in the nigral neurons of PD. These abnormalities can trigger apoptotic cell death. The primary events which induce mitochondrial failure and oxidative damage are not known, however, it has been postulated that the interaction of genetic risk factors and environmental factors would initiate the degenerative process. Based on this assumption, we conducted genetic association studies by the candidate gene methods. We found that polymorphic mutations of superoxide dismutase-2 and 24-kDa subunit of mitochondrial complex I were associated increased risk of developing Parkinson's disease. While we were doing this genetic association study, we found a family, in which parkinsonian phenotype completely segregated with a polymorphic mutation of the superoxide dismutase-2 gene. In this family, 4 out of 6 siblings were affected with early onset parkinsonism and the parents were apparently normal. Thus the mode of inheritance appeared to be autosomal recessive and this type is now called as AR-JP or Park2. We confirmed the linkage of this type of familial Parkinson's disease to the superoxide dismutase loci that is located in the telomeric region of chromosome 6 by the linkage analysis using microsatellite markers in this region. Then we found another family, in which an affected patient showed lack of one of the microsatellite markers (D6S315), which we were using in the linkage analysis. This observation prompted us to initiate the molecular cloning of the disease gene utilizing D6S315 as the initial probe. The molecular cloning was done with the collaboration with Professor Nobuyoshi Shimizu of Keio University. We identified a novel gene and confirmed that mutations of this novel gene were found only in the patients with autosomal recessive Parkinson's disease. The novel gene was named parkin. We conducted mutational analysis on more than 700 families with Parkinson's disease. We also established a method to detect compound heterozygotes of parkin mutations. Mutinous of the parkin gene were found in approximately 50% of autosomal recessive families. Many kinds of exonic deletions and point mutations were found. This type of familial Parkinson's disease had been considered to be unique among Japanese, but since we started mutational analysis of the parkin gene, we confirmed the world wide distribution of parkin gene mutations. Then we analyzed functions of parkin protein with the collaboration with Dr. Keiji Tanaka of Tokyo Metropolitan Institute of Medical Sciences. We found that parkin protein was a ubiquitin-protein ligase of the ubiquitin system. Now we are working on the candidate substrates of parkin protein as a ubiquitin ligase. We found that CDCrel-1, a synaptic vesicle protein, was a candidate substrate of parkin protein. In addition, we found two additional candidate proteins, i.e., alpha-synuclein 22 and PAEL receptor, with the collaboration of Professor Denis Selkoe of Harvard Medical School and Dr. Ryosuke Takahashi of RIKEN, respectively. Accumulation of PAEL receptor in the endoplasmic reticulum causes endoplasmic reticulum stress and apoptotic cell death. We found evidence to indicate accumulation of PAEL receptor and the presence of endoplasmic reticulum stress in a patient with AR-JP (Park2). Thus our studies firmly established that a genetic defect of an enzyme in the ubiquitin-proteasome system induces selective nigral neuronal death. We indicated the important role of the ubiquitin-proteasome system in neurodegeneration in general. In many other neurodegenerative disorders, such as Alzheimer's disease, Huntington's disease, Machado-Joseph disease, dentatorubral-pallidoluysian atrophy, and ALS, ubiquitinated proteins are accumulated in neurons. Thus protein handling in the ubiquitin-proteasome system appears to be affected in these neurodegenerative disorders despite the difference in the primary defects. Our studies also suggest many potential approaches for the discovery of neuroprotective treatment for not only Parkinson's disease but also other neurodegenerative disorders.
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PMID:[Etiology and pathogenesis of Parkinson's disease: from mitochondrial dysfunctions to familial Parkinson's disease]. 1528 6

The spinocerebellar ataxias (SCAs) are progressive neurodegenerative disorders linked to more than 20 genetic loci. Most often, these diseases are caused by expansion of triplet repeats encoding polyglutamine (polyQ) tracts. The phenotype is variable and can cause a disease that overlaps clinically with Parkinson's disease (PD). l-Dopa-responsive parkinsonism with minimal cerebellar deficits has been described in SCA2 and SCA3. In order to define if mutation at these loci is a common cause of clinically defined parkinsonism we typed the SCA-2 and SCA-3 repeats for expansion in a series of 280 patients diagnosed with PD or parkinsonism. We identified one pathogenic expansion in SCA-2 in a North American family with autosomal dominant parkinsonism.
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PMID:Analysis of SCA-2 and SCA-3 repeats in Parkinsonism: evidence of SCA-2 expansion in a family with autosomal dominant Parkinson's disease. 1591 Nov 47

SCA6 is a slowly progressive, late-onset cerebellar ataxia due to a trinucleotide expansion in the CACNA1A gene. We describe two unrelated cases that presented with Parkinsonism and cerebellar ataxia. One case was L-dopa-responsive with a pattern of (18)F-dopa uptake similar to Parkinson's disease, and the second case was not L-dopa-responsive and had an atypical pattern of nigrostriatal dysfunction. We suggest that SCA6, in common with SCA2 and SCA3, may be associated with Parkinsonism attributable to nigral loss and dopaminergic dysfunction. Moreover, isolated cases may be confused with multiple system atrophy.
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PMID:Parkinsonism and nigrostriatal dysfunction are associated with spinocerebellar ataxia type 6 (SCA6). 1595 36

Recent reports of SCA2 and SCA3 patients who presented with levodopa responsive parkinsonism have generated considerable interest as they have implications for genetic testing. It is unclear whether ethnic race alone or founder effects within certain geographical region explain such an association. In this study, we conducted genetic analysis of SCA2, 3, 17 in an ethnic Chinese cohort with early onset and familial Parkinson's disease (PD) and healthy controls. A total of 191 subjects comprising of 91 PD and 100 healthy controls were examined. We identified one positive case of SCA2 in an early-onset sporadic PD patient who had CAG 36 repeats, yielding a prevalence of 2.2% in early-onset sporadic PD patients and less than 1.0% in our study PD population. The size of the repeats was lower than the expanded repeats (38-57) in SCA2 patients with ataxia in our population. All the children of the patient were physically normal even though some of them carried the repeat expansion of similar size. No cases and controls were positive for SCA3 and SCA17. We do not think routine screening of SCA2, SCA3 and SCA17 for all idiopathic PD patients is cost-effective in our ethnic Chinese population. However, SCA2 should be a differential diagnosis in young onset sporadic PD when genetic mutations of other known PD genes have been excluded.
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PMID:Genetic analysis of SCA2, 3 and 17 in idiopathic Parkinson's disease. 1668 13

We here summarize the results of genetic investigations on a series of 82 parkinsonian patients from 60 families in Taiwan. We found 13 parkin patients in 7 families (12%), 2 PINK1 sibs from 1 family, and 1 LRRK2 patient from 1 family with I2012T mutation. We also identified SCA2 in 8 patients from 5 families (8%) and SCA3 in 3 patients from 1 family, all presenting with parkinsonian phenotype. In the available patients with parkin, PINK1, SCA2 and SCA3, the dopamine transporter (DAT) scan revealed that the reduction of uptake was primarily observed in the bilateral putamen, basically sharing a similar pattern with that in idiopathic Parkinson's disease. We concluded that the genetic causes contributed to about 25% of our series of familial parkinsonism. The parkin mutations and SCA2 were the most frequent genetic causes in our series with Chinese ethnicity. The results of DAT scan indicated that bilateral putamen was essentially involved in various genetically-caused familial parkinsonism.
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PMID:Genetic and DAT imaging studies of familial parkinsonism in a Taiwanese cohort. 1701 35

Intracellular protein misfolding/aggregation are features of many late-onset neurodegenerative diseases, called proteinopathies. These include Alzheimer's disease, Parkinson's disease, tauopathies, and polyglutamine expansion diseases [e.g., Huntington's disease; and various spinocerebellar ataxias (SCAs), like SCA3]. There are no effective strategies to slow or prevent the neurodegeneration resulting from these diseases in humans. The mutations causing many proteinopathies (e.g., polyglutamine diseases and tauopathies) confer novel toxic functions on the specific protein, and disease severity frequently correlates with the expression levels of the protein. Thus, the factors regulating the synthesis and clearance of these aggregate-prone proteins are putative therapeutic targets. The proteasome and autophagy-lysosomal pathways are the major routes for mutant huntingtin fragment clearance. While the narrow proteasome barrel precludes entry of oligomers/aggregates of mutant huntingtin (or other aggregate-prone intracellular proteins), such substrates can be degraded by macroautophagy (which we will call autophagy). We showed that the autophagy inducer rapamycin reduced the levels of soluble and aggregated huntingtin and attenuated its toxicity in cells, and in transgenic Drosophila and mouse models. We extended the range of intracellular proteinopathy substrates that are cleared by autophagy to a wide range of other targets, including proteins mutated in certain SCAs, forms of alpha-synuclein mutated in familial forms of Parkinson's disease, and tau mutants that cause frontotemporal dementia/tauopathy. In this chapter, we consider the therapeutic potential of autophagy upregulation for various proteinopathies, and describe how this strategy may act both by removing the primary toxin (the misfolded/aggregate-prone protein) and by reducing susceptibility to apoptotic insults.
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PMID:Aggregate-prone proteins are cleared from the cytosol by autophagy: therapeutic implications. 1711 64

Parkin-associated endothelin receptor-like receptor (Pael-R) is a substrate of the E3 ubiquitin ligase Parkin, which has been implicated in the pathogenesis of Parkinson disease. Misexpression of human Pael-R in Drosophila has been shown to induce selective loss of dopaminergic neurons, a symptom of Parkinson disease. Using this model, we investigated whether thioredoxin (TRX), an evolutionarily conserved antioxidant and molecular chaperone, could suppress the neurotoxicity induced by Pael-R. The Drosophila genome contains three TRX-encoding genes, namely TrxT, Trx-2, and dhd. When each of the TRX genes was overexpressed together with Pael-R in all neurons, the number of dopaminergic neurons and level of locomotor activity were significantly increased compared with control flies. To assess the role of the antioxidant activity of TRX in this context, we generated redox-defective mutants, TrxT(C35A) and TrxT(D26A/K57I), and coexpressed each of them with Pael-R. The mutants suppressed the Pael-R neurotoxicity similarly to wild-type TrxT, although the extent of the rescue was slightly reduced for the locomotor activity. We confirmed that both mutants remained active as chaperones, suggesting that this activity may be the major cause of the suppression. In the absence of Pael-R, overexpression of TRX in all neurons increased the level of locomotor activity in aged flies and extended the mean longevity by 15%. Furthermore, overexpression of TRX suppressed neurotoxicity in a Drosophila model of Machado-Joseph disease expressing polyglutamine. These results establish that Drosophila TRX can function as an anti-aging agent and as a suppressor of Pael-R- and poly-glutamine-induced neurotoxicity.
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PMID:Thioredoxin suppresses Parkin-associated endothelin receptor-like receptor-induced neurotoxicity and extends longevity in Drosophila. 1730 Oct 52

Recent reports suggest that CAG triplet expansions of spinocerebellar ataxia type 2 and 3 (SCA2 and SCA3) genes are the cause of typical levodopa-responsive Parkinson's disease (PD) in familial cases, several of which were ethnic Chinese. To investigate the role of SCA2 and SCA3 mutations in Chinese familial and early-onset PD patients, we analyzed CAG triplet repeat expansions of SCA2 and SCA3 genes in a cohort of 73 Taiwanese/Ethnic Chinese familial and early-onset PD patients [mean age at onset 42.70 +/- 7.17 years (mean +/- SD)]. Thirteen of them (17.8%) had positive family history. All patients received comprehensive clinical evaluation including a thorough neurological examination, laboratory tests, and neuroimaging studies to exclude secondary causes and atypical parkinsonism. The CAG repeat length in these genes was determined using polymerase chain reaction polyacrylamide gel electrophoresis. SCA2 gene CAG repeats ranged from 15 to 26 repeats with a median of 20, and SCA3 gene CAG repeats ranged from 15 to 40 with a median of 15. No long pathogenic repeats were found in either SCA2 or SCA3, although borderline CAG repeat number was detected in the SCA3 gene of four patients. Thus, mutations of SCA2 or SCA3 did not play a major role in familial or early-onset PD in our study cohort. PD patients without autosomal dominant family history or obvious cerebellar ataxia should not be candidates for routine screening of SCA2 or SCA3 mutations for cost-effectiveness.
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PMID:Lack of mutations in spinocerebellar ataxia type 2 and 3 genes in a Taiwanese (ethnic Chinese) cohort of familial and early-onset parkinsonism. 1744 Sep 47

The pathophysiology of restless legs syndrome (RLS) is associated with central dopaminergic system dysfunction leading to speculations that RLS may be common in those neurodegenerative diseases with dopaminergic cell loss. However, since RLS is a very common condition, the co-occurrence with less frequent disorders such as the neurodegenerative diseases might be a matter of chance. Currently, no data suggests that patients with sporadic and familial RLS are at increased risk for developing a neurodegenerative disease. In particular, whether RLS is associated with Parkinson's disease has not been established. Only a few studies have directly addressed this issue, and these have methodological limitations yielding conflicting results. Few studies have assessed the frequency of RLS in other neurodegenerative disorders. In several autosomal dominant spinocerebellar ataxias, particularly in Machado-Joseph disease, a higher frequency of RLS is reported than could be accounted for in the general population. Two anecdotal publications have reported the presence of RLS in patients with Huntington's disease and hereditary spastic paraparesis. There are no studies that have examined the association between RLS and other neurodegenerative diseases, such as Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. .
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PMID:Restless legs syndrome in Parkinson's disease and other neurodegenerative diseases of the central nervous system. 1753 50


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