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)

Genetic studies have led to major discoveries in the pathogenesis of various neurodegenerative diseases. Ubiquitin-positive familial frontotemporal dementia was recently found to be caused by mutations in the progranulin gene (PGRN), and the major constituent of the inclusions, TDP-43, was subsequently identified. The tau gene (MAPT) causes frontotemporal dementia with parkinsonism linked to chromosome 17. In Parkinson disease, LRRK2 mutations have emerged as a major cause of both familial and sporadic forms, adding to the previously known genes SNCA,PRKN,DJ1 and PINK1. Several genes have been implicated in Alzheimer disease, including the APP gene and the PSEN genes. Recently, variants in the sortilin-related receptor 1 gene, SORL1, were associated with Alzheimer disease.
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PMID:Etiology and pathophysiology of frontotemporal dementia, Parkinson disease and Alzheimer disease: lessons from genetic studies. 1832 68

Point mutations and copy number variations in SNCA, the gene encoding alpha-synuclein, cause familial Parkinson's disease (PD). A dinucleotide polymorphism (REP1) in the SNCA promoter may be a risk factor for common forms of PD. We studied 1,802 PD patients and 2,129 controls from the NeuroGenetics Research Consortium, using uniform, standardized protocols for diagnosis, subject recruitment, data collection, genotyping, and data analysis. Three common REP1 alleles (257, 259, and 261 bp, with control frequencies of 0.28, 0.65, and 0.06) and several rare alleles (combined frequency <0.01) were detected. We confirmed association of REP1 with PD risk [odds ratio (OR) = 0.86, P = 0.006 for 257-carriers; OR = 1.25, P = 0.022 for 261-carriers]. Using a normalization procedure, we showed that the 257 and 261 alleles are both independently associated with PD risk (for 257, P = 0.002 in overall data, 0.003 in non-familial PD, 0.001 in early-onset PD; for 261, P = 0.056 in overall data, 0.024 in non-familial PD, 0.052 in early-onset PD). The 257-associated risk was consistent with a dominant model [hazard ratio (HR) = 0.99, P = 0.91 for 257/257 vs. 257/X where X denotes all other common alleles; HR = 1.16, P = 0.004 for X/X vs. 257/X]. The 261-associated risk was consistent with a recessive model (HR = 1.89, P = 0.026 for 261/261 vs. 261/X; HR = 0.95, P = 0.42 for X/X vs. 261/X). Genotype-specific mean onset ages (+/-SD) ranged from 54.8 +/- 12.1 for 261/261 to 59.4 +/- 11.5 for 257/257, displaying a trend of decreasing onset age with increasing allele size (P = 0.055). Genetic variation in SNCA and its regulatory regions play an important role in both familial and sporadic PD.
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PMID:Genetic association between alpha-synuclein and idiopathic Parkinson's disease. 1840 44

Recent progresses in the pathogenesis of sporadic Parkinson's disease (PD) and genetics of familial PD are reviewed. There are common molecular events between sporadic and familial PD, particularly between sporadic PD and PARK1-linked PD due to alpha-synuclein (SNCA) mutations. In sporadic form, interaction of genetic predisposition and environmental factors is probably a primary event inducing mitochondrial dysfunction and oxidative damage resulting in oligomer and aggregate formations of alpha-synuclein. In PARK1-linked PD, mutant alpha-synuclein proteins initiate the disease process as they have increased tendency for self-aggregation. As highly phosphorylated aggregated proteins are deposited in nigral neurons in PD, dysfunctions of proteolytic systems, i.e. the ubiquitin-proteasome system and autophagy-lysosomal pathway, seem to be contributing to the final neurodegenerative process. Studies on the molecular mechanisms of nigral neuronal death in familial forms of PD will contribute further on the understanding of the pathogenesis of sporadic PD.
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PMID:Progress in the pathogenesis and genetics of Parkinson's disease. 1842 56

Alpha-synuclein (alpha-syn) is implicated in the pathogenesis of Parkinson's disease (PD). Mutations in alpha-syn gene or alpha-syn locus (SNCA) triplication are associated with mitochondrial abnormalities and early onset of familial PD. The goals of the present study were to examine whether alpha-syn is localized in the mitochondria of alpha-syn overexpressing cells (HEK-syn cells); and whether alpha-syn overexpression causes cells to be more vulnerable to mitochondrial toxin, rotenone. Western blotting and confocal microscopy techniques were employed to assess localization of alpha-syn in the mitochondria of HEK-293 cells that were stably transfected with human wild-type alpha-syn. The results demonstrated that the mitochondrial fractions that were isolated from HEK-syn cells showed the presence of alpha-syn, whereas, no alpha-syn was detected in the mitochondrial fractions of control HEK cells. The mitochondria of HEK-syn cells were found to be more susceptible to rotenone-induced toxicity when compared to control HEK cells. The intracellular ATP levels were significantly decreased in HEK-syn cells in response to sub toxic concentrations of rotenone. These results suggest that under overexpression conditions, alpha-syn may translocate to mitochondria and cause enhanced toxicity in response to sub toxic concentrations of mitochondrial toxins. This study has implications to the pathogenesis of familial PD where alpha-syn overexpression is mainly involved.
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PMID:Mitochondrial localization of alpha-synuclein protein in alpha-synuclein overexpressing cells. 1851 18

Alterations of brain and plasma alpha-synuclein levels and SNCA gene variability have been implicated in the pathogenesis of Parkinson's disease (PD). We therefore measured alpha-synuclein protein levels in postmortem PD and control cerebellum tissue using Western blot and investigated whether the levels correlated to SNCA genotype. We found markedly decreased alpha-synuclein levels in PD patients (n=16) compared to gender- and age-matched controls (n=14; P=0.004) normalized to alpha-tubulin. We also performed an association study of the noncoding polymorphisms rs2737029 (A/G) and rs356204 (A/G) (intron 4), and of rs356219 (T/C) (3'-region) of SNCA in a Swedish PD case-control material. Using a two-sided chi(2) test, we found significant association of rs2737029 (P=0.003; chi(2)=9.07) and rs356204 (P=0.048; chi(2)=3.91) with disease, strengthening the involvement of SNCA polymorphisms in sporadic PD. Stratification of the human postmortem brain material by genotype of the three investigated polymorphisms, did not indicate any influence of genotype on alpha-synuclein protein levels when comparing PD with controls. Taken together, our findings demonstrate that the investigated Parkinson patients have markedly reduced levels of alpha-synuclein in cerebellum, and that this reduction is general, rather then correlated to the investigated polymorphisms, although two of the polymorphisms also associated with disease in a Swedish material.
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PMID:Cerebellar alpha-synuclein levels are decreased in Parkinson's disease and do not correlate with SNCA polymorphisms associated with disease in a Swedish material. 1860 70

Mutations and copy number variation in the SNCA gene encoding the neuronal protein alpha-synuclein have been linked to familial Parkinson disease (Thomas, B., and Beal, M. F. (2007) Parkinson's disease. Hum. Mol. Genet. 16, R183-R194). The carboxyl terminus of alpha-synuclein can be phosphorylated at tyrosine 125 and serine 129, although only a small fraction of the protein is phosphorylated under normal conditions (Okochi, M., Walter, J., Koyama, A., Nakajo, S., Baba, M., Iwatsubo, T., Meijer, L., Kahle, P. J., and Haass, C. (2000) Constitutive phosphorylation of the Parkinson's disease associated alpha-synuclein. J. Biol. Chem. 275, 390-397). Under pathological conditions, such as in Parkinson disease, alpha-synuclein is a major component of Lewy bodies, a pathological hallmark of Parkinson disease, and is mostly phosphorylated at Ser-129 (Anderson, J. P., Walker, D. E., Goldstein, J. M., de Laat, R., Banducci, K., Caccavello, R. J., Barbour, R., Huang, J. P., Kling, K., Lee, M., Diep, L., Keim, P. S., Shen, X. F., Chataway, T., Schlossmacher, M. G., Seubert, P., Schenk, D., Sinha, S., Gai, W. P., and Chilcote, T. J. (2006) Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J. Biol. Chem. 281, 29739-29752). Controversy exists over the extent to which phosphorylation of alpha-synuclein and/or the visible protein aggregation in Lewy bodies are steps in disease pathogenesis, are protective, or are neutral markers for the disease process. Here we used the combination of peptide pulldown assays and mass spectrometry to identify and compare protein-protein interactions of phosphorylated and non-phosphorylated alpha-synuclein. We showed that non-phosphorylated alpha-synuclein carboxyl terminus pulled down protein complexes that were highly enriched for mitochondrial electron transport proteins, whereas alpha-synuclein carboxyl terminus phosphorylated on either Ser-129 or Tyr-125 did not. Instead the set of proteins pulled down by phosphorylated alpha-synuclein was highly enriched in certain cytoskeletal proteins, in vesicular trafficking proteins, and in a small number of enzymes involved in protein serine phosphorylation. This targeted comparative proteomics approach for unbiased identification of protein-protein interactions suggests that there are functional consequences when alpha-synuclein is phosphorylated.
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PMID:Proteomics analysis identifies phosphorylation-dependent alpha-synuclein protein interactions. 1861 64

Lewy bodies are mainly composed of alpha-synuclein (SNCA) and specific mutations in SNCA gene are related to familial forms of Parkinson's disease (PD). The purpose of our study was to generate a mouse line with A30P knock-in point mutation in SNCA gene and to test if a single point-mutation is able to turn otherwise normal SNCA into a toxic form. The behavioral profile of SNCA A30P mice was followed for 16 months. Generally, these mice are healthy and viable without any obvious abnormalities. Starting from the age of 13 months mice developed a significant deficit in motor performance tests related to nigrostriatal function (ink-test and beam walk). In other tests (motility boxes, rotarod) mice continuously performed normally. Moreover, SNCA A30P mice expressed the altered sensitivity to VMAT2 inhibitor reserpine, possibly reflecting a functional deficiency of dopamine. Indeed, mice at 15 months of age had significantly reduced levels of dopamine and its major metabolite DOPAC in the striatum, and reduced levels of dopamine in the mesolimbic system. The present study confirms that SNCA plays an important role in the development of PD and an insertion of a single point mutation is sufficient to generate age-related decline in specific motor performance. The generated mouse line has a potential to become a model for PD with comparable time course and phenotype.
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PMID:Alpha-synuclein A30P point-mutation generates age-dependent nigrostriatal deficiency in mice. 1862 40

Increased alpha-synuclein gene (SNCA) dosage due to locus multiplication causes autosomal dominant Parkinson's disease (PD). Variation in SNCA expression may be critical in common, genetically complex PD but the underlying regulatory mechanism is unknown. We show that SNCA and the heme metabolism genes ALAS2, FECH, and BLVRB form a block of tightly correlated gene expression in 113 samples of human blood, where SNCA naturally abounds (validated P = 1.6 x 10(-11), 1.8 x 10(-10), and 6.6 x 10(-5)). Genetic complementation analysis revealed that these four genes are co-induced by the transcription factor GATA-1. GATA-1 specifically occupies a conserved region within SNCA intron-1 and directly induces a 6.9-fold increase in alpha-synuclein. Endogenous GATA-2 is highly expressed in substantia nigra vulnerable to PD, occupies intron-1, and modulates SNCA expression in dopaminergic cells. This critical link between GATA factors and SNCA may enable therapies designed to lower alpha-synuclein production.
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PMID:GATA transcription factors directly regulate the Parkinson's disease-linked gene alpha-synuclein. 1866 54

Mutations in five PARK genes (SNCA, PARKIN, DJ-1, PINK1, and LRRK2) are well-established genetic causes of Parkinson disease (PD). Recently, G2385R substitution in LRRK2 has been determined as a susceptibility allele in Asian PD. The objective of this study is to determine the frequency of mutations in these PARK genes in a Korean early-onset Parkinson disease (EOPD) cohort. The authors sequenced 35 exons in SNCA, PARKIN, DJ-1, PINK1, and LRRK2 in 72 unrelated EOPD (age-at-onset <or=50) recruited from ten movement disorders clinics in South Korea. Gene dosage change of the aforementioned genes was studied using multiple ligation-dependent probe amplification. We found four patients with PARKIN mutations, which were homozygous deletion of exon 4, compound heterozygous deletion of exon 2 and exon 4, heterozygous deletion of exon 4, and heterozygous nonsense mutation (Q40X). Four patients had PINK1 mutations; a compound heterozygous mutation (N367S and K520RfsX522) and three heterozygous mutations (G32R, R279H, and F385L). A missense mutation of SNCA (A53T) was found in a familial PD with autosomal dominant inheritance. Nine patients (12.5%) had heterozygous G2385R polymorphism of LRRK2, whereas none had G2019S mutation. However, no mutations were detected in DJ-1 and UCHL1 in our series. We identified genetic variants in PARKIN, PINK1, LRRK2, and SNCA as a cause or genetic risk factors for PD in 25% of Korean EOPD, and mutation of PARKIN was the most common genetic cause.
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PMID:Analysis of PARK genes in a Korean cohort of early-onset Parkinson disease. 1870 25

Duplications and triplications of the alpha-synuclein (SNCA) gene have been reported in Parkinson's disease patients belonging to the Southern Swedish "Lister family". Further genealogical research has now shown that these individuals are descended from a large kindred characterized by Herman Lundborg in 1901-1913. In the expanded pedigree, a total of 25 individuals had Parkinson's disease with an autosomal dominant pattern of inheritance. Hereditary dementia, and, historically, dementia praecox have been described in other family members. Furthermore, an autosomal recessively inherited pediatric disease with nocturnal tonic-clonic fits, subsequent progressive myoclonus, startle reactions, tremor and muscle rigidity was described by Lundborg in the same pedigree. The entity was later designated Unverricht-Lundborg disease (ULD) or progressive myoclonus epilepsy type 1 (EPM1). However, Lundborg's clinical description of this disease, based on 17 patients within this kindred, differs from the modern definition of EPM1, which relies on patients with a mutation in the cystatin B (CSTB) gene. We hypothesize that the former pediatric disease, as well as the parkinsonism and dementia phenotypes, are associated with duplications, triplications and possibly higher-order multiplications of the alpha-synuclein (SNCA) gene. This hypothesis is supported by the distribution of afflicted family members within the pedigree and by recently obtained genealogical information.
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PMID:Alpha-synuclein multiplications with parkinsonism, dementia or progressive myoclonus? 1882 90


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