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)

We studied two candidate genes, tau (tau) and alpha-synuclein (SNCA), for evidence of linkage disequilibrium on a group of unrelated individuals with progressive supranuclear palsy (PSP) and a group of age-matched control subjects. The tau alpha1 allele and the tau alpha1alpha1 genotype were overrepresented in individuals with PSP and the tau polymorphism was in linkage disequilibrium with the PSP disease locus when a recessive inheritance model was employed. We also report a lack of evidence to support linkage disequilibrium between PSP and the SNCA candidate Parkinson's disease gene on chromosome 4q21-q23.
 ...
PMID:Progressive supranuclear gaze palsy is in linkage disequilibrium with the tau and not the alpha-synuclein gene. 944 91

Parkinson disease (PD) is a neurodegenerative disease characterized by tremor, bradykinesia, rigidity and postural instability. Post-mortem examination shows loss of neurons and Lewy bodies, which are cytoplasmic eosinophilic inclusions, in the substantia nigra and other brain regions. A few families have PD caused by mutations (A53T or A30P) in the gene SNCA (encoding alpha-synuclein). Alpha-synuclein is present in Lewy bodies of patients with sporadic PD, suggesting that alpha-synuclein may be involved in the pathogenesis of PD. It is unknown how alpha-synuclein contributes to the cellular and biochemical mechanisms of PD, and its normal functions and biochemical properties are poorly understood. To determine the protein-interaction partners of alpha-synuclein, we performed a yeast two-hybrid screen. We identified a novel interacting protein, which we term synphilin-1 (encoded by the gene SNCAIP). We found that alpha-synuclein interacts in vivo with synphilin-1 in neurons. Co-transfection of both proteins (but not control proteins) in HEK 293 cells yields cytoplasmic eosinophilic inclusions.
 ...
PMID:Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions. 1031 74

The human alpha-synuclein gene (SNCA) encodes a presynaptic nerve terminal protein that was originally identified as a precursor of the non-beta-amyloid component of Alzheimer's disease plaques. More recently, mutations in SNCA have been identified in some cases of familial Parkinson's disease, presenting numerous new areas of investigation for this important disease. Molecular studies would benefit from detailed information about the long-range sequence context of SNCA. To that end, we have established the complete genomic sequence of the chromosomal regions containing the human and mouse alpha-synuclein genes, with the objective of using the resulting sequence information to identify conserved regions of biological importance through comparative sequence analysis. These efforts have yielded approximately 146 and approximately 119 kb of high-accuracy human and mouse genomic sequence, respectively, revealing the precise genetic architecture of the alpha-synuclein gene in both species. A simple repeat element upstream of SNCA/Snca has been identified and shown to be necessary for normal expression in transient transfection assays using a luciferase reporter construct. Together, these studies provide valuable data that should facilitate more detailed analysis of this medically important gene.
 ...
PMID:Human and mouse alpha-synuclein genes: comparative genomic sequence analysis and identification of a novel gene regulatory element. 1115 17

Idiopathic Parkinson's disease (IPD), a progressive neurodegenerative disorder, is a common cause of disability. No current therapies modify disease progression. The pathological hallmarks are the presence of Lewy bodies and massive loss of dopaminergic neurons in the pars compacta of the substantia nigra. Two genes (SNCA and parkin) as well as two gene loci have now been implicated in the pathogenesis of familial PD. These represent significant progress in our understanding of the disease, considering the rarity of large families, low heritability in the general population and genetic heterogeneity. Mutations in a further gene, UCHL1, have been described in familial PD although the evidence for its role in PD is less clear. Knowledge of the genes described in PD to date should help to define molecular mechanisms of neurodegeneration in PD, as well as in other diseases where defects in protein handling may be a common feature. Nigral degeneration with Lewy body formation and the resulting clinical picture of PD may represent a final common pathway of a multifactorial disease process in which both environmental and genetic factors have a role. This review discusses the major advances in the field to date and illustrates how the existence of genetic factors has now become firmly established.
 ...
PMID:Genetics of Parkinsonism: a review. 1142 72

Mutations in the alpha-synuclein gene (SNCA) have been implicated in familial Parkinson's disease (PD) while certain polymorphic alleles at a microsatellite repeat, NACP-Rep1, located approximately 10 kb upstream of the gene, have been associated with sporadic PD. In order to study the regulation of the human alpha-synuclein gene, we performed a deletion analysis of 10.7 kb upstream of the translational start site, using the luciferase reporter assay in 293T cells and the neuroblastoma cell line SH-SY5Y. The shortest fragment, 400 bp upstream of the transcriptional start site, was sufficient for transcription in both cell lines. The other constructs led to variable expression levels, with some showing maximum expression and others showing nearly complete extinction of expression. An 880 bp fragment located approximately 10 kb upstream of the gene and containing the NACP-Rep1 polymorphism, was shown to be necessary for normal expression. Additional analysis of the NACP-Rep1 locus and surrounding DNA suggested that two domains flanking the repeat interact to enhance expression while the repeat acts as a negative modulator. Next, we measured the activity of the entire 10.7 kb upstream region in the luciferase reporter assay when each of our different NACP-Rep1 alleles were present. The expression levels varied very significantly among the different alleles over a 3-fold range in the SH-SY5Y cells but showed little or no significant variation in the 293T cells. Given that even small changes in alpha-synuclein expression may, over many decades, predispose to PD, the association of different NACP-Rep1 alleles with PD may be a consequence of polymorphic differences in transcriptional regulation of alpha-synuclein expression resulting from different NACP-Rep1 alleles.
 ...
PMID:Effect of allelic variation at the NACP-Rep1 repeat upstream of the alpha-synuclein gene (SNCA) on transcription in a cell culture luciferase reporter system. 1175 92

Alzheimer's disease(AD) is the most common form of neurodegenerative diseases that causes intellectual dysfunction. AD is a genetically heterogenous disorder. Over 100 mutations have been identified in three causative genes, i.e. amyloid protein precursor(APP), presenilin 1(PS1) and presenilin 2(PS2) genes, for early-onset autosomal dominant familial AD(FAD). Apolipoprotein E(APOE) gene has been identified as susceptibility gene for late-onset FAD. The missense mutations in the causative genes lead to abnormal APP processing with overproduction of total A beta protein or A beta 42(43) isoform. The epsilon 4 allele of APOE gene is a genetic risk factor for sporadic AD as well as FAD. Parkinson's disease(PD) is another common form of neurodegenerative disease that causes movement dysfunction. Three genes, i.e. alpha-synuclein (SNCA), parkin(PARK2), and ubiquitin carboxy-terminal hydrolase L1(UCHL1) genes, have been identified as causative genes for familial PD. The B mutation of CYP2D6 gene(CYP2D6*4 allele) is a genetic risk factor for PD. Lewy body(LB), that is an intracellular inclusion body characteristic of PD, is widely distributed in the cerebral cortex of 20 to 30% of AD patients. This disease entity is called as Lewy body variant(LBV) of AD. LBV shares the genetic risk factor with AD and PD, i.e. APOE epsilon 4 allele and CYP2D6 B mutation. Gene diagnosis is possible for familial AD and PD. APOE and CYP2D6 genotyping is also applicable to the future prediction of AD and PD, respectively.
 ...
PMID:[Gene diagnosis of Alzheimer's disease and Parkinson's disease]. 1245 76

NACP-Rep1, a polymorphic microsatellite upstream of the alpha-synuclein gene ( SNCA), consisting of the nucleotides (TC)(x)(T)(2)(TC)(y)(TA)(z)(CA)(w), has five alleles originally defined by 2-bp differences in (CA)(w). Different NACP-Rep1 alleles have been associated with sporadic Parkinson's disease in some, but not all, studies and can effect expression driven by the SNCA promoter over a three-fold range in the neuroblastoma cell line, SH-SY5Y. By analyzing children in CEPH families in which parents appeared to be homozygous for a NACP-Rep1 allele, we found that there are sequence differences within same-sized NACP-Rep1 alleles, contributed mainly by variation of the (TC)(y)(TA)(z) portion of the microsatellite repeat. To test whether these sequence differences might impact on promoter function we determined the effect of two sequence variant alleles, both of size "1", using the luciferase reporter system. There was only a very small expression difference between these two variant alleles. This finding implies that the overall length of the NACP-Rep1 allele plays the main role in the transcription regulation by the NACP-Rep1 element and suggests that functional differences due to sequence heterogeneity within NACP-Rep1 alleles of the same length are probably not confounding factors in association studies based on alleles defined by length.
 ...
PMID:Functional analysis of intra-allelic variation at NACP-Rep1 in the alpha-synuclein gene. 1292 82

The alpha-synuclein mutation Ala53Thr is associated with increased oligomerization, toxicity, and early onset Parkinson disease in humans, but 53Thr is the normal residue in other species. Comparative sequencing of SNCA genes shows that 53Ala marks the divergence of Old World and New World primates, in an otherwise constrained protein region. These results have implications for interpreting Parkinson disease models and suggest that other long-lived mammals have different mechanisms to forestall alpha-synucleinopathy.
 ...
PMID:alpha-Synuclein A53T substitution associated with Parkinson disease also marks the divergence of Old World and New World primates. 1502 96

The authors recently demonstrated that genetic triplication of the SNCA locus causes Parkinson disease. Here it is shown that SNCA triplication results in a doubling in the amount of alpha-synuclein protein in blood. Examination of brain tissue showed a doubling in the level of SNCA message. However, at the protein level in brain, there was a greater effect on deposition of aggregated forms into insoluble fractions than on net expression of soluble alpha-synuclein.
 ...
PMID:Alpha-synuclein in blood and brain from familial Parkinson disease with SNCA locus triplication. 1515 88

Missense mutations and genomic multiplications of the alpha-synuclein gene (SNCA) have been linked to autosomal dominant familial Parkinson's disease. We screened 50 probands of families with autosomal dominant parkinsonism for alpha-synuclein mutations by exon sequencing. No known or novel mutations were found. We also analyzed the genomic DNA for multiplications of the SNCA locus using multiplex panels of microsatellite markers. All samples were diploid with two normal copies of the SNCA locus. Hence, alpha-synuclein missense mutations and SNCA genomic multiplications remain a rare cause of disease.
 ...
PMID:Alpha-synuclein missense and multiplication mutations in autosomal dominant Parkinson's disease. 1530 6


1 2 3 4 5 6 7 8 9 10 Next >>