Involvement of aberrant glycosylation in phosphorylation of tau by cdk5 and GSK‐3β

FEBS Letters

Gong, Cheng-Xin¹  Liu, Fei¹  Grundke-Iqbal, Inge¹  Iqbal, Khalid¹ 

[1] Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA

关键词: Tau;    Glycosylation;    Phosphorylation;    Cyclin-dependent kinase 5;    Glycogen synthase kinase-3β;    Alzheimer's disease;    AD;    Alzheimer's disease;    AD-tau;    AD non-hyperphosphorylated tau;    cdk5;    cyclin-dependent protein kinase 5;    GSK-3β;    glycogen synthase kinase-3β;    NFT;    neurofibrillary tangle;    PHF;    paired helical filament;   

DOI  :  10.1016/S0014-5793(02)03487-7

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Microtubule-associated protein tau is abnormally hyperphosphorylated, glycosylated, and aggregated in affected neurons in the brains of individuals with Alzheimer's disease (AD). We recently found that the glycosylation might precede hyperphosphorylation of tau in AD. In this study, we investigated the effect of glycosylation on phosphorylation of tau catalyzed by cyclin-dependent kinase 5 (cdk5) and glycogen synthase kinase-3β (GSK-3β). The phosphorylation of the longest isoform of recombinant human brain tau, tau₄₄₁, at various sites was detected by Western blots and by radioimmuno-dot-blot assay with phosphorylation-dependent and site-specific tau antibodies. We found that cdk5 phosphorylated tau₄₄₁ at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3β phosphorylated all the cdk5-catalyzed sites above except Ser-235. Deglycosylation by glycosidases depressed the subsequent phosphorylation of AD-tau (i) with cdk5 at Thr-181, Ser-199, Ser-202, Thr-205, and Ser-404, but not at Thr-212; and (ii) with GSK-3β at Thr-181, Ser-202, Thr-205, Ser-217, and Ser-404, but not at Ser-199, Thr-212, Thr-231, or Ser-396. These data suggest that aberrant glycosylation of tau in AD might be involved in neurofibrillary degeneration by promoting abnormal hyperphosphorylation by cdk5 and GSK-3β.

【 授权许可】

Unknown