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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Glutamate-responsive translation of dendritic GSK3 beta mRNA triggers a cycle for amplification of reactivated preexisting GSK3 beta that is indispensable for tau hyperphosphorylation
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Glutamate-responsive translation of dendritic GSK3 beta mRNA triggers a cycle for amplification of reactivated preexisting GSK3 beta that is indispensable for tau hyperphosphorylation

机译：树突式GSK3βmRNA的谷氨酸响应性翻译触发了用于扩增Reactiveed预先存在的GSK3β的循环，这对于Tau超磷酸化是必不可少的

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摘要

The molecular mechanism responsible for hyperphosphorylated tau accumulation in dendrites of Alzheimer's disease (AD) neurons has not been fully clarified. Recently, we reported that tau mRNA is distributed into dendrites, and that translation and phosphorylation of tau protein are immediately enhanced in response to glutamatergic stimulation. Here, we focused on dendritic glycogen synthase kinase 3 beta (GSK3 beta), a key enzyme for tau phosphorylation, and investigated the mechanism responsible for the neural stimulation-induced hyperphosphorylation of the newly translated dendritic tau protein. We found that GSK3 beta mRNA was also distributed into dendrites of cultured hippocampal neurons, and that a glutamate-dependent slight increase of translation occurred in a short time. Concomitantly, dephosphorylation at the Ser9 residue of the preexisting GSK3 beta, which reactivates this kinase, was strongly induced without an increase of its phosphatase PP1 or a decrease of the PP1 inhibitor I-2. Instead, I-2 phosphorylation was observed, suggesting disinhibition of PP1. This glutamate dependent phosphorylation of I-2 and the dephosphorylation of preexisting GSK3 beta were abolished in the presence of GSK3 beta inhibitors. Interestingly, translational obstruction of GSK3 beta mRNA also canceled these reactions. These results indicate that dendrites exhibit a glutamate-responsive cycle for amplification of reactivated preexisting GSK3 beta operating via PP1 disinhibition, whose activation requires neural activity-dependent translation of dendritic GSK3 beta mRNA. This would explain why a slight increase of dendritic GSK3 beta is sufficient to trigger hyperphosphorylation of significantly increased tau protein.
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