α-Synuclein promoter RsaI T-to-C polymorphism and the risk of Parkinson’s disease

Wang, Chun-Kai; Chen, C. M.; Chang, C. Y.; Chang, Kuo‐Hsuan; Chen, I. C.; Li, M. L.; Lee‐Chen, Guey‐Jen; Wu, Yih‐Ru

doi:10.1007/s00702-006-0435-4

Cited by 17 publications

(13 citation statements)

References 29 publications

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“…In recent years, substantial evidence has confirmed that variants in the promoter of certain genes may underlie the pathogenesis of several neurological diseases, including Parkinson's disease [Wang et al, 2006], Huntington's disease [Coles et al, 1998], and AD [Fallin et al, 2001;Heijmans et al, 2002]. Very recent studies provide strong evidence that an APP promoter polymorphism, which has a higher transcriptional activity, over-expresses APP [Lv et al, 2008].…”

Section: Discussionmentioning

confidence: 97%

A megalin polymorphism associated with promoter activity and Alzheimer's disease risk

Vargas

Bullido

Martínez-García

et al. 2010

American J of Med Genetics Pt B

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Elevated cerebral levels of amyloid beta-protein (Abeta) occur in Alzheimer's disease (AD), yet only a few patients show evidence of increased Abeta production. This observation suggests that many, perhaps most, cases of AD are caused by faulty clearance of Abeta. Megalin, which plays an important role in mediating Abeta clearance, is an attractive candidate gene for genetic association with AD. To investigate this hypothesis, we analyzed the megalin gene in a population of 2,183 subjects. Genetic analysis indicated that the rs3755166 (G/A) polymorphism located in the megalin promoter associated with risk for AD, dependently of apolipoprotein E genotype. The rs3755166 AA genotype frequency was significantly greater in AD patients than in control subjects. Furthermore, the luciferase reporter assay indicated that the rs3755166 A variant has 20% less transcriptional activity than the rs3755166 G variant. This study provides strong evidence that this megalin polymorphism confers a greater risk for AD, and supports a biological role for megalin in the neurodegenerative processes involved in AD.

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Section: Discussionmentioning

confidence: 97%

A megalin polymorphism associated with promoter activity and Alzheimer's disease risk

Vargas

Bullido

Martínez-García

et al. 2010

American J of Med Genetics Pt B

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“…Families with mutated α-syn exhibit autosomal dominant PD (Athanassiadou et al, 1999;Kruger et al, 1998;Polymeropoulos et al, 1997;Zarranz et al, 2004), and gene multiplication leading to increased wildtype α-syn levels also causes disease (Singleton et al, 2003). Certain α-syn promoter polymorphisms are PD risk factors, suggesting that even modest increases in expression can predispose to disease (Farrer et al, 2001;Kruger et al, 1999;Pals et al, 2004;Tan et al, 2000;Wang et al, 2006). In patients without genetic mutations, α-syn is found in Lewy bodies and degenerating neurites (Irizarry et al, 1998;Spillantini et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional dysregulation in a transgenic model of Parkinson disease

Yacoubian

Cantuti-Castelvetri

Bouzou

et al. 2008

Neurobiology of Disease

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Alpha-synuclein has been implicated in Parkinson's disease, yet the mechanism by which alphasynuclein causes cell injury is not understood. Using a transgenic mouse model, we evaluated the effect of alpha-synuclein overexpression on gene expression in the substantia nigra. Nigral mRNA from wildtype and alpha-synuclein transgenic mice was analyzed using Affymetrix gene arrays. At three months, before pathological changes are apparent, we observed modest alterations in gene expression. However, nearly 200 genes were altered in expression at nine months, when degenerative changes are more apparent. Functional genomic analysis revealed that the genes altered at nine months were predominantly involved in gene transcription. As in human Parkinson's disease, gene expression changes in the transgenic model were also modulated by gender. These data demonstrate that alterations of gene expression are widespread in this animal model, and suggest that transcriptional dysregulation may be a disease mechanism that can be targeted therapeutically.

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“…Previously, we reported that the À110 A/C may be a functional polymorphism in the 5 0 promoter region of HSP70-1 and may affect the susceptibility to PD [Wu et al, 2004], that RsaI T-to-C substitution may have a functional relevance to the susceptibility of PD [Wang et al, 2006] and that tumor necrosis factor-a promoter polymorphism, À1031 CC, is associated with the risk of PD . Given that multi-factors involving both genetics and environment are implicated in the pathogenesis of PD, in the present study, we examined the impact of BDNF and NR4A2 genetic variations on the susceptibility to Taiwanese PD.…”

Section: Discussionmentioning

confidence: 99%

“…A portion of the subjects had been enrolled in three previously reported studies [Wu et al, 2004Wang et al, 2006]. All patients exhibited at least two of the four cardinal signs of PD: resting tremor, cogwheel rigidity, bradykinesia, and postural reflex impairment; all were diagnosed with probable idiopathic PD according to the published criteria [Gelb et al, 1999].…”

Section: Subjectsmentioning

confidence: 99%

Nuclear receptor NR4A2 IVS6 +18insG and brain derived neurotrophic factor (BDNF) V66M polymorphisms and risk of Taiwanese parkinson's disease

Chen

Chang

et al. 2007

American J of Med Genetics Pt B

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Both of environmental and genetic factors confer vulnerability to Parkinson's disease (PD). NR4A2 (Nurr1), a member of the steroid/thyroid hormone nuclear receptor superfamily, is essential for the neurogenesis and differentiation of dopaminergic neurons in the midbrain. Brain derived neurotrophic factor (BDNF) deficiency may play a role in the pathogenesis of PD, as the surviving dopaminergic nigrostriatal neurons have reduced levels of BDNF. This study examines whether BDNF V66M (c.196 G --> A) or NR4A2 IVS6 +18insG polymorphism is associated with the risk of Taiwanese PD and the age of onset using a case-control study. The genotype or allele frequency distribution of both BDNF V66M and NR4A2 IVS6 +18insG polymorphisms was not significantly different between the cases and the controls. Neither BDNF nor NR4A2 polymorphism influences PD onset age. Notably, after stratification by sex, female individuals carrying the NR4A2 2G/2G genotype demonstrated a trend toward significant decrease in risk of developing PD (OR = 0.49, 95% CI = 0.25-0.96, P = 0.039). These results suggest that the NR4A2 IVS6 +18insG polymorphism may play a minor role in PD susceptibility among Taiwanese women.

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α-Synuclein promoter RsaI T-to-C polymorphism and the risk of Parkinson’s disease

Cited by 17 publications

References 29 publications

A megalin polymorphism associated with promoter activity and Alzheimer's disease risk

A megalin polymorphism associated with promoter activity and Alzheimer's disease risk

Transcriptional dysregulation in a transgenic model of Parkinson disease

Nuclear receptor NR4A2 IVS6 +18insG and brain derived neurotrophic factor (BDNF) V66M polymorphisms and risk of Taiwanese parkinson's disease

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