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)

To this day, the cause of multiple system atrophy (MSA) remains stubbornly enigmatic. A growing body of observations regarding the clinical, morphological, and biochemical phenotypes of MSA has been published, but the interested student is still left without a clue as to its underlying cause. MSA has long been considered a rare cousin of Parkinson's disease and cerebellar degeneration; it is rich in acronyms but poor in genetic and environmental leads. Because of the worldwide research efforts conducted over the last two decades and the discovery of the alpha-synuclein-encoding SNCA gene as a cause of rare familial Parkinson's disease, the MSA field has seen advances on three fronts: the identification of its principal cellular target, that is, oligodendrocytes; the characterization of alpha-synuclein-rich glial cytoplasmic inclusions as a suitable marker at autopsy; and improved diagnostic accuracy in living patients resulting from detailed clinicopathological studies. The working model of MSA as a primary glial disorder was recently strengthened by the finding of dysregulation in the metabolism of myelin basic protein and p25alpha, a central nervous system-specific phosphoprotein (also called tubulin polymerization promoting protein, TPPP). Intriguingly, in early cases of MSA, the oligodendrocytic changes in myelin basic protein and p25alpha processing were recorded even before formation of glial cytoplasmic inclusions became detectable. Here, we review the evolving concept that MSA may not just be related to Parkinson's disease but also share traits with the family of demyelinating disorders. Although these syndromes vary in their respective cause of oligodendrogliopathy, they have in common myelin disruption that is often followed by axonal dysfunction.
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PMID:Multiple system atrophy: a primary oligodendrogliopathy. 1882 60

In Parkinson's disease (PD) neuronal degeneration is associated with abnormal protein aggregation in various forms including Lewy bodies (LBs). A major component of LBs is alpha-synuclein; septin 4 (SEPT4), a polymerizing GTP-binding protein that serves as scaffold for diverse molecules has been found to colocalize with alpha-synuclein in LBs. The central role of SEPT4 in the etiopathogenesis of PD has been suggested since SEPT4 also shows a physiological association with alpha-synuclein and serves as a substrate for parkin. To this end, we studied the expression of septin 4 and alpha-synuclein in postmortem human substantia nigra (SN) and amygdala from patients with PD and healthy controls. Twenty patients (14 men : 6 women, onset 63.0 +/- 11.4 years, age 77.3 +/- 7.6 years, Hoehn and Yahr 4.05/5) and 9 neurologically healthy controls (4 men/5 women, age at death 80.1 +/- 8.6 years) were studied. Sporadic PD cases showed a statistically significant decrease of the fold change (FC) of SNCA (FC = 0.31, P = 0.00001) and SEPT4 (FC = 0.67, P = 0.054) gene expressions in the SN and the amygdala (SNCA: FC = 0.49, P = 0.02; SEPT4: FC = 0.32, P = 0.007) versus healthy controls. However, an increase of both proteins in PD versus control subjects was observed with immunoblotting. The semi-quantitative protein ratio calculations revealed more than 10-fold increases for both SEPT4 and alpha-synuclein in PD versus control subjects. We present for the first time similar signal expression patterns and parallel accumulation of SEPT4 and alpha-synuclein in well-characterized postmortem PD brain. Considering the heterogeneous etiology of sporadic PD and the variability of individual human samples, SEPT4 accumulation may be regarded as one of the common pathological changes in PD and should therefore be further explored.
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PMID:Expression of Lewy body protein septin 4 in postmortem brain of Parkinson's disease and control subjects. 1895 7

Early onset Parkinson's disease (EOPD) has been associated with mutations in the Parkin, DJ-1, PINK1, LRRK2, and SNCA genes. The aim of this study is to assess the contribution of these genes in a Dutch EOPD cohort and the phenotypic characteristics of the mutation carriers. A total of 187 unrelated Dutch EOPD patients (age at onset < or = 50 years) were phenotyped and screened for mutations in all exons of Parkin, DJ-1, and PINK1 by direct sequencing and gene dosage analysis. Additionally, analysis of the A30P mutation and exon dosage of SNCA and sequencing of exons 19,31,35,38,41, and 48 of LRRK2 was performed. Pathogenic variations could explain disease in 4% (7 of 187) of the patients including five patients carrying homozygous or compound heterozygous mutations in Parkin, one with a novel homozygous deletion in DJ-1 (P158Del) and one with a heterozygous mutation in LRRK2 (T2356I). We found seven novel mutations. The phenotypic characteristics of mutation carriers varied widely, comparable to the variability seen in sporadic EOPD. Parkin is the most frequently mutated gene in this EOPD cohort, followed by DJ-1, PINK1 and LRRK2. The low overall mutation frequency indicates that the extrapolation of mutation frequencies from other populations should be applied with caution.
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PMID:Genotypic and phenotypic characteristics of Dutch patients with early onset Parkinson's disease. 1897 54

Parkinson disease (PD) is associated with progressive loss of dopaminergic neurons in the substantia nigra, as well as with more-widespread neuronal changes that cause complex and variable motor and nonmotor symptoms. Recent rapid advances in PD genetics have revealed a prominent role for mitochondrial dysfunction in the pathogenesis of the disease, and the products of several PD-associated genes, including SNCA, Parkin, PINK1, DJ-1, LRRK2 and HTR2A, show a degree of localization to the mitochondria under certain conditions. Impaired mitochondrial function is likely to increase oxidative stress and might render cells more vulnerable to this and other related processes, including excitotoxicity. The mitochondria, therefore, represent a highly promising target for the development of disease biomarkers by use of genetic, biochemical and bioimaging approaches. Novel therapeutic interventions that modify mitochondrial function are currently under development, and a large phase III clinical trial is underway to examine whether high-dose oral coenzyme Q10 will slow disease progression. In this Review, we examine evidence for the roles of mitochondrial dysfunction and increased oxidative stress in the neuronal loss that leads to PD and discuss how this knowledge might further improve patient management and aid in the development of 'mitochondrial therapy' for PD.
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PMID:Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. 1897

Five genes have been identified that contribute to Mendelian forms of Parkinson disease (PD); however, mutations have been found in fewer than 5% of patients, suggesting that additional genes contribute to disease risk. Unlike previous studies that focused primarily on sporadic PD, we have performed the first genomewide association study (GWAS) in familial PD. Genotyping was performed with the Illumina HumanCNV370Duo array in 857 familial PD cases and 867 controls. A logistic model was employed to test for association under additive and recessive modes of inheritance after adjusting for gender and age. No result met genomewide significance based on a conservative Bonferroni correction. The strongest association result was with SNPs in the GAK/DGKQ region on chromosome 4 (additive model: p = 3.4 x 10(-6); OR = 1.69). Consistent evidence of association was also observed to the chromosomal regions containing SNCA (additive model: p = 5.5 x 10(-5); OR = 1.35) and MAPT (recessive model: p = 2.0 x 10(-5); OR = 0.56). Both of these genes have been implicated previously in PD susceptibility; however, neither was identified in previous GWAS studies of PD. Meta-analysis was performed using data from a previous case-control GWAS, and yielded improved p values for several regions, including GAK/DGKQ (additive model: p = 2.5 x 10(-7)) and the MAPT region (recessive model: p = 9.8 x 10(-6); additive model: p = 4.8 x 10(-5)). These data suggest the identification of new susceptibility alleles for PD in the GAK/DGKQ region, and also provide further support for the role of SNCA and MAPT in PD susceptibility.
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PMID:Genomewide association study for susceptibility genes contributing to familial Parkinson disease. 1898 86

Patients with Leucine-rich repeat kinase 2 (LRRK2) linked Parkinson's disease (PD) clinically present with typical idiopathic PD. However, LRRK2-linked PD displays a pleomorphic neuropathology and high variability in age at disease onset (AAO) which suggests that environmental and/or genetic factors other than the mutation itself influence the course of the disease. We investigated the modulation of AAO by genetic factors including the mutation-containing domain and PD associated polymorphisms in the gene coding alpha-synuclein (SNCA) and tau (MAPT) in 44 patients from 19 affected families. Using this limited number of available LRRK2 mutation carriers, we provide evidence that mutations in the kinase domain of Lrrk2 significantly decrease AAO compared to mutations in the ROC (Ras/GTPase of complex proteins) domain. Furthermore, polymorphic variations in MAPT show a significant association with AAO in individuals with LRRK2 mutations. Our results await replication in future studies with a larger number of LRRK2 mutation carriers, but indicate an association of mutation-affected protein domain and mutation-extrinsic genetic factors with AAO and suggest that these factors could contribute to explain the phenotypic heterogeneity observed in LRRK2-linked PD.
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PMID:Genetic factors influencing age at onset in LRRK2-linked Parkinson disease. 1904 Dec 74

Levodopa is the most effective medication for Parkinson's disease (PD). In contrast, there is evidence that levodopa and its metabolites such as dopa/dopamine quinone are toxic for nigral neurons based on in vitro studies. Moreover, there is growing evidence that oxidative stress and mitochondrial dysfunction contribute the pathogenesis of PD. Thus, studies for oxidative stress give us good information for elucidating the pathogenesis of PD. In this regard, it is mandatory to develop markers such as 4-hydroxy-nonenal (HNE). HNE is a product of lipid peroxidation. Indeed, immunohistochemical studies have revealed that HNE-modified proteins accumulate within ragged red fibers (RRFs). This finding indicated that mitochondrial impairment may be linked to oxidative stress. Moreover, HNE-modified proteins accumulate in nigral neurons. In PD, mitochondrial dysfunction such as complex I deficiency has also been reported. In addition, HNE can modify alpha-synuclein (SNCA). Subsequently, this modification may trigger the aggregation of this protein. At a minimum, this modification could be associated with oligomer formation or fibrillation of SNCA.
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PMID:Toxic effects of dopamine metabolism in Parkinson's disease. 1913 Oct 41

The pre-synaptic protein alpha-synuclein is a key player in the pathogenesis of Parkinson's disease (PD). Misfolded alpha-synuclein protofibrils accumulate and serve as seed structures that cause numerous proteins in the cytoplasm of neuronal cells to aggregate into so-called Lewy bodies. Furthermore, both missense mutations and multiplications of the SNCA gene lead to autosomal dominant forms of familial PD. However, the exact biological role of alpha-synuclein in normal brains remains elusive. To gain more insight into the normal function of this protein, we evaluated changes in whole genome expression in dopaminergic neuroblastoma cells (SH-SY5Y) caused by reductions of 90% in alpha-synuclein RNA levels and of 59% in alpha-synuclein protein levels as a result of RNA interference. The expression of 361 genes was altered at least+/-1.5-fold by the RNA interference, with 82 up-regulated and 279 down-regulated. The differentially expressed gene products are involved in the regulation of transcription, cell cycle, protein degradation, apoptosis, neurogenesis, and lipid metabolism. To examine the influence of SNCA down-regulation by RNAi on apoptosis, we performed cell death assays using different stress triggers. The changes observed in the expression profile of dopaminergic neuronal cells following reduction of SNCA expression warrant studies to investigate the role of signaling cascades in familial and idiopathic PD.
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PMID:Microarray expression analysis of human dopaminergic neuroblastoma cells after RNA interference of SNCA--a key player in the pathogenesis of Parkinson's disease. 1913 32

Whole-genome epistasis analysis may add a new layer of knowledge to whole-genome association studies, permitting the identification of new candidate genes which are completely transparent during conventional single-locus analysis. We present the first whole-genome conditional two-locus analysis in Parkinson's disease (PD). We scanned the entire genome and selected markers that interacted with a set of well-known loci previously associated to PD (SNCA, Parkin, LRRK2, UCHL1, DJ-1, PINK and MAPT). Our work describes several loci potentially related to PD risk which interact with SNCA, PARK1 and LRRK2 markers. We propose conditional whole-genome two-locus association analysis as a valuable method that might be helpful in re-analysing and re-interpreting data from whole-genome association studies.
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PMID:Whole-genome conditional two-locus analysis identifies novel candidate genes for late-onset Parkinson's disease. 1915 51

Parkinson's disease (PD) is characterized by accumulation of alpha-synuclein (alpha-syn) and degeneration of neuronal populations in cortical and subcortical regions. Mitochondrial dysfunction has been considered a potential unifying factor in the pathogenesis of the disease. Mutations in genes linked to familial forms of PD, including SNCA encoding alpha-syn and Pten-induced putative kinase 1 (PINK1), have been shown to disrupt mitochondrial activity. We investigated the mechanisms through which mutant Pink1 might disrupt mitochondrial function in neuronal cells with alpha-syn accumulation. For this purpose, a neuronal cell model of PD was infected with virally-delivered Pink1, and was analyzed for cell survival, mitochondrial activity and calcium flux. Mitochondrial morphology was analyzed by confocal and electron microscopy. These studies showed that mutant (W437X) but not wildtype Pink1 exacerbated the alterations in mitochondrial function promoted by mutant (A53T) alpha-syn. This effect was associated with increased intracellular calcium levels. Co-expression of both mutant Pink1 and alpha-syn led to alterations in mitochondrial structure and neurite outgrowth that were partially ameliorated by treatment with cyclosporine A, and completely restored by treatment with the mitochondrial calcium influx blocker Ruthenium Red, but not with other cellular calcium flux blockers. Our data suggest a role for mitochondrial calcium influx in the mechanisms of mitochondrial and neuronal dysfunction in PD. Moreover, these studies support an important function for Pink1 in regulating mitochondrial activity under stress conditions.
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PMID:Mutant Pink1 induces mitochondrial dysfunction in a neuronal cell model of Parkinson's disease by disturbing calcium flux. 1916 11


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