GSK3Bpolymorphisms alter transcription and splicing in Parkinson's disease
In: Annals of Neurology, Jg. 58 (2005-12-01), Heft 6, S. 829-839
Online
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Zugriff:
Parkinson's disease (PD) is a neurodegenerative disorder characterized by a combination of motor symptoms. We identified two functional single nucleotide polymorphisms in the glycogen synthase kinase‐3β gene (GSK3B). A promoter single nucleotide polymorphism (rs334558) is associated with transcriptional strength in vitro in which the T allele has greater activity. An intronic single nucleotide polymorphism (rs6438552) regulates selection of splice acceptor sites in vitro. The T allele is associated with altered splicing in lymphocytes and increased levels of GSK3Btranscripts that lack exons 9 and 11 (GSKΔexon9+11). Increased levels of GSKΔexon9+11 correlated with enhanced phosphorylation of its substrate, Tau. In a comparison of PD and control brains, there was increased in frequency of T allele (rs6438552) and corresponding increase in GSKΔexon9+11 and Tau phosphorylation in PD brains. Conditional logistic regression indicated gene–gene interaction between T/T genotype of rs334558 and H1/H1 haplotype of microtubule‐associated protein Tau (MAPT) gene (p= 0.009). There was association between a haplotype (T alleles of both GSK3Bpolymorphisms) and disease risk after stratification by Tau haplotypes ((H1/H2+H2/H2 individuals: odds ratio, 1.64; p= 0.007; (H1/H1 individuals: odds ratio, 0.68; p< 0.001). Ours results suggest GSK3Bpolymorphisms alter transcription and splicing and interact with Tau haplotypes to modify disease risk in PD. Ann Neurol 2005;58:829–839
Titel: |
GSK3Bpolymorphisms alter transcription and splicing in Parkinson's disease
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Autor/in / Beteiligte Person: | Kwok, John B. J. ; Hallupp, Marianne ; Loy, Clement T. ; Chan, Daniel K. Y. ; Woo, Jean ; Mellick, George D. ; Buchanan, Daniel D. ; Silburn, Peter A. ; Halliday, Glenda M. ; Schofield, Peter R. |
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Zeitschrift: | Annals of Neurology, Jg. 58 (2005-12-01), Heft 6, S. 829-839 |
Veröffentlichung: | 2005 |
Medientyp: | serialPeriodical |
ISSN: | 0364-5134 (print) ; 1531-8249 (print) |
DOI: | 10.1002/ana.20691 |
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