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Novel therapeutic strategies for neurodegenerative disease
Author(s) -
TANIMUKAI Hitoshi,
KUDO Takashi,
TANAKA Toshihisa,
GRUNDKEIQBAL Inge,
IQBAL Khalid,
TAKEDA Masatoshi
Publication year - 2009
Publication title -
psychogeriatrics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.647
H-Index - 32
eISSN - 1479-8301
pISSN - 1346-3500
DOI - 10.1111/j.1479-8301.2009.00289.x
Subject(s) - protein phosphatase 2 , protein subunit , cytoplasm , hyperphosphorylation , phosphorylation , phosphatase , nls , amino acid , nuclear localization sequence , cleavage (geology) , microbiology and biotechnology , chemistry , biology , biochemistry , gene , paleontology , fracture (geology)
The activity of protein phosphatase 2A (PP2A) is compromised and believed to be the cause of the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain. Activity of PP2A is regulated by two endogeneous inhibitor proteins, called as I 1 PP2A and I 2 PP2A . Previously, we reported that: (i) I 1 PP2A and I 2 PP2A are upregulated with cleavage of I 2 PP2A holoprotein and translocation of its amino terminal fragment from the nucleus to the cytoplasm in neuronal cells in AD brains; and (ii) translocated I 2 PP2A colocalized not only with the PP2A catalytic subunit, but also with phosphorylated tau in neuronal cytoplasm. Furthermore, according to preliminary data, the cleavage site of I 2 PP2A is located between amino acids 175 and 176 of the I 2 PP2A sequence. Because the sequence from amino acids 168 to 181 on I 2 PP2A presumably functions as a nuclear localization signal (NLS), inhibition of break down of the NLS in I 2 PP2A is expected to be a novel therapeutic target for the treatment of Alzheimer's disease.