Cytoplasmic Retention of Protein Phosphatase 2A-Inhibitor 2 (I2PP2A) Induces Alzheimer-like Abnormal Hyperphosphorylation of Tau [Cell Biology]

August 15th, 2014 by Arif, M., Wei, J., Zhang, Q., Liu, F., Basurto-Islas, G., Grundke-Iqbal, I., Iqbal, K.

Abnormal hyperphosphorylation of tau leads to the formation of neurofibrillary tangles, a hallmark of Alzheimer disease (AD), and related tauopathies. The phosphorylation of tau is regulated by protein phosphatase 2A (PP2A) which in turn is modulated by endogenous inhibitor-2 (I2PP2A). In AD brain, I2PP2A is translocated from neuronal nucleus to cytoplasm where it inhibits PP2A activity and promotes abnormal phosphorylation of tau. Here we describe the identification of a potential nuclear localization signal (NLS) in the C-terminal region of I2PP2A containing a conserved basic motif, 179KRK181 which is sufficient for directing its nuclear localization. The current study further presents an inducible cell model (Tet-Off system) of AD-type abnormal hyperphosphorylation of tau by expressing I2PP2A in which the NLS was inactivated by 179KRK181-AAA along with 168KR169-AA mutations. In this model, the mNLS-I2PP2A (I2PP2AAA-AAA) was translocated from nucleus to the cytoplasm where it physically interacted with PP2A and inhibited its activity. Inhibition of PP2A was associated with the abnormal hyperphosphorylation of tau, which resulted in microtubule network instability and neurite outgrowth impairment. Expression of mNLS-I2PP2A activated CAMKII and GSK-3β, which are tau kinases regulated by PP2A. The immunoprecipitation experiments showed the direct interaction of I2PP2A with PP2A and GSK-3β but not with CAMKII. Thus, the cell model provides insights into the nature of the potential NLS and the mechanistic relationship between cytoplasmic translocation of I2PP2A induced inhibition of PP2A and hyperphosphorylation of tau that can be utilized to develop drugs preventing tau pathology.
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