%0 Journal Article %J J Alzheimers Dis %D 2016 %T UCH-L1 Inhibition Decreases the Microtubule-Binding Function of Tau Protein. %A Xie, Min %A Han, Yun %A Yu, Quntao %A Wang, Xia %A Wang, Shaohui %A Liao, Xiaomei %K Animals %K Cell Line, Tumor %K Dose-Response Relationship, Drug %K HEK293 Cells %K Humans %K Immunoprecipitation %K Indoles %K Mice %K Microtubules %K Neuroblastoma %K Oximes %K Protein Binding %K Proteolysis %K RNA, Small Interfering %K tau Proteins %K Ubiquitin Thiolesterase %K Ubiquitination %X

Ubiquitin C-terminal hydrolase L1 (UCH-L1) is critical for protein degradation and free ubiquitin recycling. In Alzheimer's disease brains, UCH-L1 is negatively related to neurofibrillary tangles whose major component is hyperphosphorylated tau protein, but the direct action of UCH-L1 on tau has not been reported. In the current study, mouse neuroblastoma Neuro2a (N2a) cells were treated by the different concentrations of UCH-L1 inhibitor LDN (2.5, 5 and 10 μM) to inhibit the hydrolase activity of UCH-L1. In addition, we also used UCH-L1 siRNA to treat the HEK293/tau441 cells to decrease the expression of UCH-L1. After LDN and UCH-L1 siRNA treatment, we used immunofluorescence, immunoprecipitation, and tau-microtubule binding assay to measure the microtubule-binding ability and post-translational modifications of tau protein. All the results presented that both inhibition of the activity and expression of UCH-L1 induced the decreased microtubule-binding ability and increased phosphorylation of tau protein. Abnormal aggregation and ubiquitination of tau protein was also observed after UCH-L1 inhibition. The above results suggested that aggregation of tau protein might be devoted to the abnormal post-translational modifications of tau protein. Our study first indicates that dysfunction of UCH-L1 most likely affected normal biological function of tau protein through decreasing degradation of ubiquitinated and hyperphosphorylated tau.

%B J Alzheimers Dis %V 49 %P 353-63 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444754?dopt=Abstract %R 10.3233/JAD-150032