DEPHOSPHORYLATION OF ALZHEIMERS-DISEASE ABNORMALLY PHOSPHORYLATED-TAU BY PROTEIN PHOSPHATASE-2A

被引:149
作者
GONG, CX [1 ]
GRUNDKEIQBAL, I [1 ]
IQBAL, K [1 ]
机构
[1] NEW YORK STATE INST BASIC RES DEV DISABIL,NEW YORK,NY 10314
关键词
D O I
10.1016/0306-4522(94)90400-6
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Microtubule-associated protein tau is abnormally hyperphosphorylated in the brain of patients with Alzheimer's disease, and is the major protein subunit of paired helical filaments. There is also a significant pool of non-paired helical filament abnormally phosphorylated tau in Alzheimer's disease brain. In the present study, the site-specific dephosphorylation of this Alzheimer's disease abnormally phosphorylated tau by protein phosphatase-2A was studied and compared with that by protein phosphatase-2B. The dephosphorylation was detected by its interaction with several phosphorylation-dependent antibodies to various abnormal phosphorylation sites. Protein phosphatase-2A was able to dephosphorylate the abnormally phosphorylated tau at Ser-46, Ser-199, Ser-202, Ser-396 and Ser-404, but not at Ser-235 (the amino acids are numbered according to the largest isoform of human tau, tau(441)). Two major types of protein phosphatase-2A, protein phosphatase-2A(1) and -2A(2), dephosphorylated the abnormally phosphorylated tau at approximately the same rate. After the abnormally phosphorylated tau was dephosphorylated by protein phosphatase-2A, its relative mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis increased. The dephosphorylation of the abnormal tau by protein phosphatase-2A(1) and -2A(2) was markedly stimulated by Mn2+. These results suggest that tau dephosphorylation is catalysed by protein phosphatase-2A in addition to protein phosphatase-2B. A deficiency of either protein phosphatase-2A or -2B, or both, may be involved in abnormal phosphorylation of tau in Alzheimer's disease.
引用
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页码:765 / 772
页数:8
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