Showing papers by "John B.J. Kwok published in 2005"
TL;DR: Results suggest GSK3B polymorphisms alter transcription and splicing and interact with Tau haplotypes to modify disease risk in PD.
Abstract: 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-3beta 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 GSK3B transcripts that lack exons 9 and 11 (GSKDeltaexon9+11). Increased levels of GSKDeltaexon9+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 GSKDeltaexon9+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 GSK3B polymorphisms) 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 GSK3B polymorphisms alter transcription and splicing and interact with Tau haplotypes to modify disease risk in PD.
204 citations
TL;DR: A family with a PS‐1 M146L mutation and both Pick bodies and AD is described, which may predispose to both Pick's disease and AD by affecting multiple intracellular pathways involving tau phosphorylation and amyloid metabolism.
Abstract: Presenilin-1 (PS-1) mutations can cause Pick's disease without evidence of Alzheimer's disease (AD). We describe a family with a PS-1 M146L mutation and both Pick bodies and AD. Sarkosyl-insoluble hyperphosphorylated tau showed three bands consistent with AD, although dephosphorylation showed primarily three-repeat isoforms. M146L mutant PS-1 may predispose to both Pick's disease and AD by affecting multiple intracellular pathways involving tau phosphorylation and amyloid metabolism.
57 citations
TL;DR: The APP 693 mutation at position 22 of the Abetapeptide resulting in a glutamine for glutamic acid was identified in the proband and the affected sister and highlights the importance of detecting this rare cause of fatal cerebral haemorrhage.
10 citations