Abstract
The microtubule-associated protein tau gene (MAPT) codes for a protein that plays an integral role in stabilisation of microtubules and axonal transport in neurons. As well as its role in susceptibility to neurodegeneration, previous studies have found an association between the MAPT haplotype and intracranial volume and regional grey matter volumes in healthy adults. The glycogen synthase kinase-3β gene (GSK3B) codes for a serine/threonine kinase that phosphorylates various proteins, including tau, and has also been associated with risk for neurodegenerative disorders and schizophrenia. We examined the effects of MAPT and two functional promoter polymorphisms in GSK3B (rs3755557 and rs334558) on total grey matter and intracranial volume in three independent cohorts totaling 776 neurologically healthy individuals. In vitro analyses revealed a significant effect of rs3755557 on gene expression, and altered binding of at least two transcription factors, Octamer transcription factor 1 (Oct-1) and Pre-B-cell leukemia transcription factor 1 (Pbx-1), to the GSK3B promoter. Meta-analysis across the three cohorts revealed a significant effect of rs3755557 on total grey matter volume (summary B = 0.082, 95% confidence interval = 0.037–0.128) and intracranial volume (summary B = 0.113, 95% confidence interval = 0.082–0.144). No significant effect was observed for MAPT H1/H2 diplotype or GSK3B rs334558 on total grey matter or intracranial volume. Our genetic and biochemical analyses have identified a role for GSK3B in brain development, which could have important aetiological implications for neurodegenerative and neurodevelopmental disorders.
Highlights
Microtubule-associated protein tau is a phosphorylated protein highly expressed in brain, where it assists in stabilisation of the cytoskeleton and axonal transport in neurons [1]
Analysis of rs3755557 Effect on Promoter Function For this study, we defined the minor alleles of rs3755557 and rs334558 according to the nucleotide sequence on the plus strand of chromosome 3 as to be consistent with the single nucleotide polymorphisms (SNPs) annotations in public databases [23], i.e. the opposite orientation as the GSK3B gene, so that the minor allele for rs3755557 = A and rs334558 = G
We examined whether grey matter volume or intracranial volume differed significantly by microtubule-associated protein tau gene (MAPT) H1/H2 diplotype or GSK3B genotypes in three Magnetic Resonance Imaging (MRI) cohorts by linear regression analysis (Table 2, Table S1 in Information S1 and Table S2 in Information S1)
Summary
Microtubule-associated protein tau is a phosphorylated protein highly expressed in brain, where it assists in stabilisation of the cytoskeleton and axonal transport in neurons [1]. Neurofibrillary tangles of hyperphosphorylated tau are a pathological hallmark of several neurodegenerative disorders, including Alzheimer’s disease and frontotemporal dementia [2]. H1/H2 haplotypes have been shown to affect expression and/ or splicing of MAPT [6,7,8,9,10] and have been associated with risk of several sporadic neurodegenerative disorders, including Alzheimer’s disease [11], progressive supranuclear palsy [12], corticobasal degeneration [13] and Parkinson’s disease [14]. Polymorphisms in the gene encoding GSK-3b (GSK3B) have been associated with Alzheimer’s disease and frontotemporal dementia [17,18], and an epistatic interaction between GSK3B and MAPT has been associated with Parkinson’s disease and Alzheimer’s disease [9,19,20]. The minor allele of rs334558 (in European populations) [23] is predicted to abrogate binding of transcription factor AP4 and was associated with a decrease in gene expression relative to the major allele [20]
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