Title | UCH-L1 Inhibition Decreases the Microtubule-Binding Function of Tau Protein. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Xie, M, Han, Y, Yu, Q, Wang, X, Wang, S, Liao, X |
Journal | J Alzheimers Dis |
Volume | 49 |
Issue | 2 |
Pagination | 353-63 |
Date Published | 2016 |
ISSN | 1875-8908 |
Keywords | Animals, Cell Line, Tumor, Dose-Response Relationship, Drug, HEK293 Cells, Humans, Immunoprecipitation, Indoles, Mice, Microtubules, Neuroblastoma, Oximes, Protein Binding, Proteolysis, RNA, Small Interfering, tau Proteins, Ubiquitin Thiolesterase, Ubiquitination |
Abstract | 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. |
DOI | 10.3233/JAD-150032 |
Alternate Journal | J. Alzheimers Dis. |
PubMed ID | 26444754 |