Restoration of biological activity of Alzheimer abnormally phosphorylated tau by dephosphorylation with protein phosphatase-2A, -2B and -1.
Microtubule associated protein tau promotes the assembly of microtubules by binding to microtubules and stabilizing their structure. In Alzheimer disease brain, tau is abnormally hyperphosphorylated and the altered tau is unable to promote the in vitro assembly of microtubules. In the present study, we found that dephosphorylation of abnormally phosphorylated tau by protein phosphatase-2A1, -2B or -1 restored its biological activity both in the nucleation and in the assembly of microtubules. Both the amount of phosphate released and the rate of restoration of microtubule assembly promoting activity of the abnormal tau were greater on dephosphorylation by protein phosphatase-2A1 than -2B or -1. During 90 min incubation at 37 degrees C protein phosphatase-2A1, -2B and -1 released respectively approximately 57%, approximately 36% and approximately 30% of tau phosphate. Association of the restoration of the biological activity of the abnormal tau dephosphorylated by different phosphatases and the immunochemical identification of the dephosphorylated sites revealed that Ser-235 is not critical in tau function, and that the Thr-231 is probably involved in the regulation of the nucleation and not the assembly of microtubules. These studies indicate that the phosphorylation of tau in situ might be regulated by protein phosphatase-2A, -2B and -1 and activation of these enzyme activities might arrest the Alzheimer neurofibrillary degeneration.
Wang
J Z
JZ
New York State Institute for Basic Research in Developmental Disabilities, Staten Island 10314, USA.
Grundke-Iqbal
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D000469:Alkaline Phosphatase / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008870:Microtubules / Q000648:ultrastructure*; D010710:Phosphates / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D013912:Threonine / Q000737:chemistry; D016875:tau Proteins / Q000378:metabolism*
D010710:Phosphates; D016875:tau Proteins; D013912:Threonine; D000469:Alkaline Phosphatase; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2