-Synuclein and Parkinson disease susceptibility

Department of Neurology, University of Lübeck
Neurology (Impact Factor: 8.29). 10/2007; 69(18):1745-50. DOI: 10.1212/01.wnl.0000275524.15125.f4
Source: PubMed

ABSTRACT Mutations in the alpha-synuclein (SNCA) gene have been shown to be responsible for a rare familial form of Parkinson disease (PD). Furthermore, polymorphic variants in multiple regions of the gene have been associated with susceptibility to idiopathic PD in different populations.
To evaluate and to confirm the role of SNCA variants in PD pathogenesis.
We included 667 subjects (397 cases with idiopathic PD and 270 healthy, ethnically matched controls) of Northern Central and Southeastern European origin. We analyzed genotypes at 14 markers spanning the SNCA locus and its major haplotype blocks and conducted a haplotype analysis for four promoter markers including the microsatellite marker Rep1.
The three single nucleotide polymorphisms (SNPs) of the promoter region (rs2583988, rs2619364, rs2619363) and a SNP in the 3'UTR (rs356165) of the SNCA gene showed the greatest evidence for an association with PD (p <or= 0.003), with significant pairwise values for linkage disequilibrium (D' >or= 0.74, r (2) >or= 0.29). The promoter haplotype "261-T-G-T" (Rep1-rs2583988-rs2619364-rs2619363) was associated with disease (p = 0.032). The most significant association with PD was generated by excluding Rep1 (p = 0.008). This association remained significant when analyzing the Serbian patients separately and was of borderline significance for the German patients.
Our findings confirm that genetic variability within the SNCA locus is associated with susceptibility to idiopathic Parkinson disease (PD). We found evidence for disease association with single nucleotide polymorphisms at both the 5' and the 3' end of the gene with pairwise linkage disequilibrium between them. The association was independent of the Rep1 status, and one major SNCA promoter haplotype class seems to be associated with PD susceptibility.

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Available from: Kristoffer Haugarvoll, Sep 29, 2015
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    • "At the same time, the presence of the Rep1—259 allele has been demonstrated to correlate with a low level of SNCA mRNA in post mortem brain tissues of patients with PD [18]. It was shown that Rep1 is associated with rs2583988, rs2619363 and rs2619364, and that these polymorphic variants are in a strong linkage disequilibrium (LD: r 2 = 0.99, D' = 1.00) [19] [20]. In studies of patients with PD from Europe (Belgium, Germany and Serbia), an association of these polymorphisms with the risk of PD was identified [20- 22]. "
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    ABSTRACT: Parkinson’s disease (PD) is one of the most common human neurodegenerative disorders caused by the loss of dopaminergic neurons in the brain. The α-synuclein (SNCA) gene is one of the most studied genes involved in the pathogenesis of PD. In our study, we conducted a genetic analysis of promoter and intron single-nucleotide polymorphisms (SNPs) in the SNCA gene. We also analyzed the association of genotypes of these SNPs with expression levels of SNCA mRNA. One of the four SNPs in the SNCA gene, the rs2736990 polymorphism, associates with the risk of the sporadic form of PD in Russian population. The risk of PD was increased almost twofold in carriers of allele C (odds ratios = 1.9, 95% confidence interval: 1.24 - 2.91, p = 0.003). However, no association was found between any of the genotypes of SNPs tested (rs2583988, rs2619363, rs2619364 and rs2736990) and alterations in SNCA levels. Our findings support the hypothesis that the rs2736990 polymorphism is associated with PD. SNPs rs2583988, rs2619363 and rs2619364 in the promoter region of the SNCA gene themselves, and do not significantly influence the expression of SNCA. Most likely, SNCA gene expression is a very complex process that is affected by different genetic and epigenetic factors.
    Neuroscience & Medicine 12/2013; 4(4):208-214. DOI:10.4236/nm.2013.44032
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    • "Interestingly, SNCA duplications were also reported in four apparently sporadic PD patients (Ahn et al., 2008; Nishioka et al., 2009). Common variability within the promoter or 3′-UTR of SNCA is associated with increased α-synuclein expression and a greater risk of sporadic PD (Mueller et al., 2005; Pals et al., 2004; Winkler et al., 2007). "
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    ABSTRACT: Parkinson's disease (PD) is the second most common neurodegenerative disease. The gradual, irreversible loss of dopamine neurons in the substantia nigra is the signature lesion of PD. Clinical symptoms of PD become apparent when 50-60% of nigral dopamine neurons are lost. PD progresses insidiously for 5-7 years (preclinical period) and then continues to worsen even under the symptomatic treatment. To determine what triggers the disease onset and what drives the chronic, self-propelling neurodegenerative process becomes critical and urgent, since lack of such knowledge impedes the discovery of effective treatments to retard PD progression. At present, available therapeutics only temporarily relieve PD symptoms. While the identification of causative gene defects in familial PD uncovers important genetic influences in this disease, the majority of PD cases are sporadic and idiopathic. The current consensus suggests that PD develops from multiple risk factors including aging, genetic predisposition, and environmental exposure. Here, we briefly review research on the genetic and environmental causes of PD. We also summarize very recent genome-wide association studies on risk gene polymorphisms in the emergence of PD. We highlight the new converging evidence on gene-environment interplay in the development of PD with an emphasis on newly developed multiple-hit PD models involving both genetic lesions and environmental triggers.
    Progress in Neurobiology 03/2011; 94(1):1-19. DOI:10.1016/j.pneurobio.2011.03.005 · 9.99 Impact Factor
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    • "To what concerns autosomal dominant PD, such a unifying picture is not available so far, however it appears that any process controlling the concentration of ␣-synuclein may potentially affect the pathogenetic oligomerization of the protein. This includes mutations (PARK1) or covalent modifications (e.g., by dopamine quinone species) that improve amyloidogenesis, duplication and triplication of the ␣synuclein gene (PARK4), proteasomal and autophagic/lysosomal impairment, regulation of expression at the transcriptional level (Cookson and Bandmann, 2010; Cuervo et al., 2010; Dawson et al., 2010; Hardy, 2010; Hastings, 2009; Maraganore et al., 2006; Sutherland et al., 2009; Winkler et al., 2007). "
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