Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, New York, United States of America.
PLoS One. 2012;7(2):e31152. doi: 10.1371/journal.pone.0031152. Epub 2012 Feb 15.
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.
微管结合蛋白 Tau 的过度磷酸化是包括阿尔茨海默病在内的许多神经退行性疾病的一个特征。在依赖于品系的方式下，dab1 基因敲除小鼠的海马体中 Tau 发生过度磷酸化；然而，目前还不清楚 Tau 磷酸化表型是否是这些突变体发病的次要效应。dab1 基因编码一种对接蛋白，作为 Reelin 信号通路的一部分，是正常大脑分层和树突发生所必需的。我们发现，在大脑发育后敲除 dab1 基因会导致解剖学上正常的小鼠 Tau 过度磷酸化。先前已经确定了调节 dab1 突变体中磷酸化 Tau 表型的基因组区域。通过在高磷酸化 Tau 表达和低磷酸化 Tau 表达的 dab1 突变体之间进行微阵列基因表达比较，我们鉴定出 Stk25 是 dab1 突变体表型的差异表达修饰因子。Stk25 的敲低减少了胚胎神经元中的 Tau 磷酸化。此外，Stk25 以拮抗的方式调节神经元极化和高尔基形态。这项工作深入了解了大脑发育过程中神经元行为的复杂调节，并为调节 Tau 磷酸化的分子级联提供了新的认识。
