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Identification of Stk25 as a genetic modifier of Tau phosphorylation in Dab1-mutant mice.

Matsuki, T; Zaka, M; Guerreiro, R; van der Brug, MP; Cooper, JA; Cookson, MR; Hardy, JA; (2012) Identification of Stk25 as a genetic modifier of Tau phosphorylation in Dab1-mutant mice. PLoS One , 7 (2) , Article e31152. 10.1371/journal.pone.0031152. Green open access

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Abstract

Hyperphosphorylation of the microtubule binding protein Tau is a feature of a number of neurodegenerative diseases, including Alzheimer's disease. Tau is hyperphosphorylated in the hippocampus of dab1-null mice in a strain-dependent manner; however, it has not been clear if the Tau phosphorylation phenotype is a secondary effect of the morbidity of these mutants. The dab1 gene encodes a docking protein that is required for normal brain lamination and dendritogenesis as part of the Reelin signaling pathway. We show that dab1 gene inactivation after brain development leads to Tau hyperphosphorylation in anatomically normal mice. Genomic regions that regulate the phospho Tau phenotype in dab1 mutants have previously been identified. Using a microarray gene expression comparison between dab1-mutants from the high-phospho Tau expressing and low-phospho Tau expressing strains, we identified Stk25 as a differentially expressed modifier of dab1-mutant phenotypes. Stk25 knockdown reduces Tau phosphorylation in embryonic neurons. Furthermore, Stk25 regulates neuronal polarization and Golgi morphology in an antagonistic manner to Dab1. This work provides insights into the complex regulation of neuronal behavior during brain development and provides insights into the molecular cascades that regulate Tau phosphorylation.

Type: Article
Title: Identification of Stk25 as a genetic modifier of Tau phosphorylation in Dab1-mutant mice.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0031152
Publisher version: http://dx.doi.org/10.1371/journal.pone.0031152
Language: English
Additional information: © 2012 Matsuki et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PMCID: PMC3280280 This work was supported by National Institute of Neurological Disorders and Stroke intramural and State University of New York, Upstate Medical University startup funds for BWH, National Institutes of Health grant CA41072 to JAC, and National Institute on Aging intramural funds for MRC. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.
Keywords: Animals, Biological Markers, Blotting, Western, Brain, Cells, Cultured, Female, Gene Expression Profiling, Genes, Modifier, HeLa Cells, Humans, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Nerve Tissue Proteins, Neurons, Oligonucleotide Array Sequence Analysis, Phosphorylation, Protein-Serine-Threonine Kinases, RNA, Messenger, RNA, Small Interfering, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Tyrosine, tau Proteins
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/1340431
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