title: Cytoplasmic retention of protein phosphatase 2A inhibitor 2 (I2PP2A) induces Alzheimer-like abnormal hyperphosphorylation of Tau.
abstract: 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 (I2 (PP2A)). In AD brain, I2 (PP2A) 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 I2 (PP2A) containing a conserved basic motif, (179)RKR(181), 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 I2 (PP2A) in which the NLS was inactivated by (179)RKR(181) → AAA along with (168)KR(169) → AA mutations. In this model, the mutant NLS (mNLS)-I2 (PP2A) (I2 (PP2A)AA-AAA) was retained in the cell 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-I2 (PP2A) activated CAMKII and GSK-3β, which are Tau kinases regulated by PP2A. The immunoprecipitation experiments showed the direct interaction of I2 (PP2A) 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 I2 (PP2A)-induced inhibition of PP2A and hyperphosphorylation of Tau that can be utilized to develop drugs preventing Tau pathology.
authors.affiliation: From the Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Arif
authors.affiliation: From the Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314.
authors.forename: Jianshe
authors.initials: J
authors.lastname: Wei
authors.affiliation: From the Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: From the Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: From the Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Basurto-Islas
authors.affiliation: From the Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314.
authors.forename: Inge
authors.initials: I
authors.lastname: Grundke-Iqbal
authors.affiliation: From the Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314 khalid.iqbal.ibr@gmail.com.
authors.forename: Khalid
authors.initials: K
authors.lastname: Iqbal
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D056488:Histone Chaperones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019913:Nuclear Localization Signals; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D056488:Histone Chaperones; C054369:MAPT protein, human; D019913:Nuclear Localization Signals; C513473:SET protein, human; D014157:Transcription Factors; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2
keywords: Alzheimer Disease; Ca2+/Calmodulin-dependent Protein Kinase (CaMK); Protein Serine/Threonine Phosphatase (PSP); Serine/Threonine Protein Kinase; Tau Protein (Tau)