Inhibition of cyclin-dependent kinase 5 but not of glycogen synthase kinase 3-β prevents neurite retraction and tau hyperphosphorylation caused by secretable products of human T-cell leukemia virus type I-infected lymphocytes
| Autor: | Luis Cartier, Elias Utreras, L. Collados, Javier Puente, Horacio Maldonado, A.M. Kettlun, Ashok B. Kulkarni, Mario Chiong, María Elsa Pando, M.A. Valenzuela, Eugenio Ramírez |
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| Rok vydání: | 2011 |
| Předmět: |
SH-SY5Y
Neurite T-Lymphocytes Hyperphosphorylation tau Proteins macromolecular substances Biology Statistics Nonparametric Article Biological Factors Glycogen Synthase Kinase 3 Neuroblastoma Cellular and Molecular Neuroscience GSK-3 Neurites Tumor Cells Cultured Humans Phosphorylation GSK3B Analysis of Variance Human T-lymphotropic virus 1 Glycogen Synthase Kinase 3 beta Kinase Cyclin-dependent kinase 5 Cyclin-Dependent Kinase 5 Neurodegenerative Diseases Gene Products tax Molecular biology Biochemistry Culture Media Conditioned |
| Zdroj: | JOURNAL OF NEUROSCIENCE RESEARCH Artículos CONICYT CONICYT Chile instacron:CONICYT |
| ISSN: | 0360-4012 |
| Popis: | Human T-cell leukemia virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease characterized by selective loss of axons and myelin in the corticospinal tracts. This central axonopathy may originate from the impairment of anterograde axoplasmic transport. Previous work showed tau hyperphosphorylation at T(181) in cerebrospinal fluid of HAM/TSP patients. Similar hyperphosphorylation occurs in SH-SY5Y cells incubated with supernatant from MT-2 cells (HTLV-I-infected lymphocytes secreting viral proteins, including Tax) that produce neurite shortening. Tau phosphorylation at T(181) is attributable to glycogen synthase kinase 3-β (GSK3-β) and cyclin-dependent kinase 5 (CDK5) activation. Here we investigate whether neurite retraction in the SH-SY5Y model associates with concurrent changes in other tau hyperphosphorylable residues. Threonine 181 turned out to be the only tau hyperphosphorylated residue. We also evaluate the role of GSK3-β and CDK5 in this process by using specific kinase inhibitors (LiCl, TDZD-8, and roscovitine). Changes in both GSK3-β active and inactive forms were followed by measuring the regulatory phosphorylable sites (S(9) and Y(216) , inactivating and activating phosphorylation, respectively) together with changes in β-catenin protein levels. Our results showed that LiCl and TDZD-8 were unable to prevent MT-2 supernatant-mediated neurite retraction and also that neither Y(216) nor S(9) phosphorylations were changed in GSK3-β. Thus, GSK3-β seems not to play a role in T(181) hyperphosphorylation. On the other hand, the CDK5 involvement in tau phosphorylation was confirmed by both the increase in its enzymatic activity and the absence of MT-2 neurite retraction in the presence of roscovitine or CDK5 siRNA transfection. |
| Databáze: | OpenAIRE |
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