title: 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.
abstract: 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.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
authors.forename: Horacio
authors.initials: H
authors.lastname: Maldonado
authors.forename: Eugenio
authors.initials: E
authors.lastname: Ramírez
authors.forename: Elias
authors.initials: E
authors.lastname: Utreras
authors.forename: María E
authors.initials: ME
authors.lastname: Pando
authors.forename: Ana M
authors.initials: AM
authors.lastname: Kettlun
authors.forename: Mario
authors.initials: M
authors.lastname: Chiong
authors.forename: Ashok B
authors.initials: AB
authors.lastname: Kulkarni
authors.forename: Lucía
authors.initials: L
authors.lastname: Collados
authors.forename: Javier
authors.initials: J
authors.lastname: Puente
authors.forename: Luis
authors.initials: L
authors.lastname: Cartier
authors.forename: María A
authors.initials: MA
authors.lastname: Valenzuela
mesh_terms: D000704:Analysis of Variance; D001685:Biological Factors / Q000378:metabolism / Q000502:physiology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D016356:Gene Products, tax / Q000378:metabolism / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D015368:Human T-lymphotropic virus 1 / Q000472:pathogenicity*; D006801:Humans; D016501:Neurites / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D009447:Neuroblastoma; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000473:pathology / Q000821:virology*; D010766:Phosphorylation / Q000187:drug effects; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D014407:Tumor Cells, Cultured; D016875:tau Proteins / Q000378:metabolism
chemical_list: D001685:Biological Factors; D017077:Culture Media, Conditioned; D016356:Gene Products, tax; D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3