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)

The recent discovery of two mutations associated with autosomal dominant Parkinson's disease (PD) has led to the hypothesis that the alpha-synuclein gene plays a role in the pathogenesis of PD. Here we report a novel triplet CAA repeat within the unusually large intron 5 sequence of the alpha-synuclein gene. Microsatellite analysis revealed a high degree of polymorphism within the Irish population with seven alleles detected, ranging from eight to 17 CAA repeats. Analysis of the allele/genotype frequency differences observed between an Irish idiopathic PD cohort (eta = 98) and a healthy aged control group ( eta= 92) revealed no strong association with either group. All PD subjects displaying homozygous profiles were examined for expansion of the trinucleotide repeat, but no expansion was observed. These results would suggest that polymorphism of the alpha-synuclein gene may not play as significant a role in the pathogenesis of idiopathic PD as previously hypothesised.
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PMID:A novel polymorphic triplet repeat in intron five of the alpha-synuclein gene: no evidence of expansion or allelic association with idiopathic Parkinson's disease in the Irish. 1235 14

Spinocerebellar ataxia type 2 (SCA2) has been recognized recently as an uncommon cause of parkinsonism, an alternate presentation to the typical cerebellar disorder. This research review summarizes the existing literature on parkinsonism-predominant presentation SCA2 and presents new clinical cases of patients with this condition. Various phenotypes are noted in this subtype of SCA2, including parkinsonism indistinguishable from idiopathic Parkinson's disease (PD), parkinsonism plus ataxia, motor neuron disease, and postural tremor. In several kindreds with multiple affected family members, the SCA2 expansion segregated with disease; in addition, several single cases of parkinsonism with and without a family history are also described. The number of repeats in symptomatic patients ranged from 33 to 43. Interruption of the CAG repeat with CAA, CGG, or CCG was found in some individuals, possibly stabilizing the repeat structure and accounting for the relative stability of the repeat size across generations in some families; allele length is not necessarily indicative of trinucleotide repeat architecture. Positron emission tomography scanning in one family showed reduced fluorodopa uptake and normal to increased raclopride binding with a rostrocaudal gradient similar to that found in idiopathic PD. This review emphasizes the importance of testing for SCA2 in patients with parkinsonism and a family history of neurodegenerative disorders. Testing for SCA2 is also important in studies of inherited parkinsonism.
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PMID:Profile of families with parkinsonism-predominant spinocerebellar ataxia type 2 (SCA2). 1519 99

Trinucleotide repeat (TNR) expansion in the gene for TATA binding protein (TBP) has recently been described as causal for spinocerebellar ataxia type 17. The normal number of repeats has been considered to be 42 or less. An intermediate range with reduced penetrance has been assumed to be 43-47 CAA/CAG repeats. We examined this gene in 30 patients with autosomal-dominant cerebellar ataxia (ADCA), 35 patients with sporadic ataxia, 11 patients with Huntington's disease (HD), 351 patients with idiopathic Parkinson's disease (PD), 105 patients with Alzheimer's disease (AD), and 291 controls with no history of neurodegenerative disease. Three patients (one with sporadic PD and two with AD) carrying more than 42 TNRs in the TBP gene were identified. This reveals that the phenotype associated with CAG/CAA expansion in the TBP gene may be heterogeneous.
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PMID:Analysis of polyglutamine-coding repeats in the TATA-binding protein in different neurodegenerative diseases. 1536 89

Destruction of nigrostriatal dopaminergic (DA) pathway triggers various persistent responses, such as inflammation and increased synthesis of neural growth factors, both in striatum and in substantia nigra. The pathological processes involved in such responses are poorly characterized and could contribute to secondary damage and/or regeneration in the central nervous system (CNS). Cystatin C was previously implicated in the process of neurodegeneration. However, its biological role during neurodegeneration is not understood and remains controversial. The present study identified an increased cystatin C mRNA level in the DA-depleted rat striatum, starting from the second week following a 6-OHDA-induced lesion. Immunohistochemical analysis confirmed the increase in cystatin C protein level in the striatum following DA depletion. Double-labeled fluorescence immunohistochemistry revealed that nigrostriatal neurons, astrocytes, and microglia contributed to the elevated level of cystatin C. Exposure to 6-hydroxydopamine, a DA-specific neurotoxin, resulted in DA neurons loss in the fetal mesencephalic cultures, an effect which could be partially reversed by treatment with cystatin C. Moreover, in vivo DA neurons survival study showed that administration of cystatin C in rats with 6-OHDA-induced lesion partially rescued the nigral DA neurons. The results indicate that the 6-OHDA lesioning induced a relatively slow but sustained up-regulation of cystatin C expression and suggest that the inhibitor may exert a neuroprotective action on DA neurons. The findings raise the possibility that cysteine proteinase inhibitors may be new candidates for neuroprotective treatment of Parkinson's disease. Cystatin C may be useful therapeutically in limiting neuropathy in Parkinson's disease.
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PMID:Cystatin C prevents degeneration of rat nigral dopaminergic neurons: in vitro and in vivo studies. 1564 6

Whereas the prevalence and impact of vascular pathology in Alzheimer diease (AD) are well established, the role of vascular and Alzheimer pathologies in the progression of neurodegeneration and cognitive impairment in Parkinson disease (PD) is under discussion. A retrospective clinico-pathologic study of 100 patients with autopsy proven PD (including 44 cases with dementia/PDD) and 20 cases of dementia with Lewy bodies (DLB) confirmed essential clinical (duration of illness, Mini-Mental State Examination/MMSE, age at death) and morphologic differences between these groups; Lewy body Braak scores and Alzheimer pathologies (neuritic Braak stage, cortical Abeta plaque load, and generalized cerebral amyloid angiopathy or CAA) were significantly higher/more severe in DLB and PDD than in PD without dementia. Duration of illness showed no association to any of the examined pathologic parameters, while there was a moderate association between LB scores and neuritic Braak stages, the latter significantly increasing with age. Significant association between cerebrovascular lesions and neuritic Braak stage was seen in PDD but not in PD subjects without dementia. These data suggest an influence of Alzheimer-related lesions on the progression of the neurodegenerative process and, in particular, on cognitive decline in both PDD and DLB. On the other hand, both these factors in PD and DLB appear to be largely independent from coexistent vascular pathology, except in cases with severe cerebrovascular lesions or those related to neuritic AD pathology. Assessment of ApoE genotype in a small number of cases showed no significant differences in the severity of Abeta plaque load and CAA except for much lower intensities in non-demented epsilon3/3 patients. Despite increasing evidence suggesting synergistic reactions between alpha-synuclein (alphaSyn), tau and Abeta-peptides, the major protein markers of both AD and Lewy body diseases, and of both vascular pathology and AD, the molecular background and pathophysiological impact of these pathologies on the progression of neurodegeneration and development of cognitive decline in PD await further elucidation.
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PMID:Prevalence and impact of vascular and Alzheimer pathologies in Lewy body disease. 1827 24

Spinocerebellar ataxia 17 (SCA17) or Huntington's disease-like-4 is a neurodegenerative disease caused by the expansion above 44 units of a CAG/CAA repeat in the coding region of the TATA box binding protein (TBP) gene leading to an abnormal expansion of a polyglutamine stretch in the corresponding protein. Alleles with 43 and 44 repeats have been identified in sporadic cases and their pathogenicity remains uncertain. Furthermore, incomplete penetrance of pathological alleles with up to 49 repeats has been suggested. The imperfect nature of the repeat makes intergenerational instability extremely rare and de novo mutations are most likely the result of partial duplications. This is one of the rarer forms of autosomal dominant cerebellar ataxia but the associated phenotype is often severe, involving various systems (cerebral cortex, striatum, and cerebellum), with extremely variable age at onset (range: 3-75 years) and clinical presentation. This gene is thought to account for a small proportion of patients with a Huntington's disease-like phenotype and cerebellar signs. Parkinson's disease-like, Creutzfeldt-Jakob disease-like and Alzheimer disease-like phenotypes have also been described with small SCA17 expansions. The abnormal protein is expressed at the same level as its normal counterpart and forms neuronal intranuclear inclusions containing other proteins involved in protein folding or degradation. The increase in the size of the glutamine stretch enhances transcription in vitro, probably leading to transcription deregulation. Interestingly, the TBP protein mutated in SCA17 is recruited in the inclusions of other polyglutaminopathies, suggesting its involvement in the transcription down-regulation observed in these diseases.
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PMID:Spinocerebellar ataxia 17 (SCA17) and Huntington's disease-like 4 (HDL4). 1841 87

The food supplement creatine (Cr) is widely used by athletes as a natural ergogenic compound. It has also been increasingly tested in neurodegenerative diseases as a potential neuroprotective agent. Weight gain is the most common side effect of Cr, but sporadic reports about the impairment of renal function cause the most concerns with regard to its long-term use. Data from randomized controlled trials on renal function in Cr-supplemented patients are scarce and apply mainly to healthy young athletes. We systematically evaluated potential side effects of Cr with a special focus on renal function in aged patients with Parkinson disease as well as its current use in clinical medical research. Sixty patients with Parkinson disease received either oral Cr (n = 40) or placebo (n = 20) with a dose of 4 g/d for a period of 2 years. Possible side effects as indicated by a broad range of laboratory blood and urine tests were evaluated during 6 follow-up study visits. Overall, Cr was well tolerated. Main side effects were gastrointestinal complaints. Although serum creatinine levels increased in Cr patients because of the degradation of Cr, all other markers of tubular or glomerular renal function, especially cystatin C, remained normal, indicating unaltered kidney function. The data in this trial provide a thorough analysis and give a detailed overview about the safety profile of Cr in older age patients.
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PMID:Long-term creatine supplementation is safe in aged patients with Parkinson disease. 1908 5

Parkinson's disease (PD) is a chronic, progressive, neurodegenerative disease with a multifactorial etiology. Protein accumulation is speculated by some to play a prominent role in the pathogenesis of PD. The severity of neurodegeneration should correlate with cerebrospinal fluid (CSF) levels of these neurodegenerative markers (NDMs). The aims of the study were to assess the CSF levels of tau protein, beta-amyloid (1-42), cystatin C, and clusterin in patients suffering from PD and in a control group, to compare the CSF levels between the two groups and to correlate them to PD duration. NDMs in the CSF were assessed in 32 patients suffering from PD and in a control group (CG) of 30 patients. The following statistically significant differences in the CSF were found: higher tau protein (p = 0.045) and clusterin levels (p = 0.004) in PD patients versus CG; higher tau protein levels (p = 0.033), tau protein/beta-amyloid (1-42) ratio (p = 0.011), and clusterin (p = 0.044) in patients suffering from PD for <2 years versus patients suffering PD for more than 2 years. No differences between beta-amyloid (1-42) and cystatin C CSF levels were found in the CG and PD patients groups. Significantly higher tau protein and clusterin CSF levels in the group of PD patients with disease duration of <2 years probably reflect the fact that most neurodegenerative changes in PD patients occur in the initial stage of disease.
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PMID:CSF markers of neurodegeneration in Parkinson's disease. 2073 May 48

Cystatin C (CC) is a cysteine protease inhibitor abundantly expressed in the central nervous system. Bunina bodies, small eosinophilic intraneuronal inclusions, are stain positive for CC and are the most specific histological hallmark of amyotrophic lateral sclerosis (ALS). In this study, employing a latex turbidimetric immunoassay, levels of CC in cerebrospinal fluid (CSF) were quantified in 130 age-matched individuals with either a neurological disorder [ALS, Alzheimer's disease (AD), Parkinson's disease (PD), tauopathy (TP), multiple system atrophy (MSA), chronic inflammatory demyelinating polyneuropathy (CIDP)] or no known neurological condition (normal control, NC). The CC level in CSF was found to be correlated with the age during the investigation but not the protein concentration. There was no difference in CC levels between NC and ALS or CIDP cases, whereas CC levels were significantly lower in MSA compared with NC. Of the 130 cases, 96 were genotyped, and G/A or A/A polymorphism at +73 within the CST3 gene was found in 28 individuals. The CC level was significantly lower in the combined group of G/A and A/A genotypes compared with G/G. The present data demonstrate that the level of CC in CSF should not be considered as a biomarker of ALS, but there is a correlation between CC levels and the CST3 genotype.
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PMID:Quantification of cystatin C in cerebrospinal fluid from various neurological disorders and correlation with G73A polymorphism in CST3. 2084 35

Neurodegeneration occurs in acute pathological conditions such as stroke, ischemia, and head trauma and in chronic disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. While the cause of neuronal death is different and not always known in these varied conditions, hindrance of cell death would be beneficial in the prevention of, slowing of, or halting disease progression. Enhanced cystatin C (CysC) expression in these conditions caused a debate as to whether CysC up-regulation facilitates neurodegeneration or it is an endogenous neuroprotective attempt to prevent the progression of the pathology. However, recent in vitro and in vivo data have demonstrated that CysC plays protective roles via pathways that are dependent on inhibition of cysteine proteases, such as cathepsin B, or by induction of autophagy, induction of proliferation, and inhibition of amyloid-beta aggregation. Here we review the data demonstrating the protective roles of CysC under conditions of neuronal challenge and the protective pathways induced under various conditions. These data suggest that CysC is a therapeutic candidate that can potentially prevent brain damage and neurodegeneration.
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PMID:Protective mechanisms by cystatin C in neurodegenerative diseases. 2119 95


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