Novel therapeutic strategies for neurodegenerative disease

Authors: TANIMUKAI, Hitoshi; KUDO, Takashi¹; TANAKA, Toshihisa¹; GRUNDKE-IQBAL, Inge²; IQBAL, Khalid²; TAKEDA, Masatoshi¹

Source: Psychogeriatrics, Volume 9, Number 2, June 2009 , pp. 103-109(7)

Publisher: Wiley-Blackwell

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Abstract:

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 I₁^PP2A and I₂^PP2A. Previously, we reported that: (i) I₁^PP2A and I₂^PP2A are upregulated with cleavage of I₂^PP2A holoprotein and translocation of its amino terminal fragment from the nucleus to the cytoplasm in neuronal cells in AD brains; and (ii) translocated I₂^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 I₂^PP2A is located between amino acids 175 and 176 of the I₂^PP2A sequence. Because the sequence from amino acids 168 to 181 on I₂^PP2A presumably functions as a nuclear localization signal (NLS), inhibition of break down of the NLS in I₂^PP2A is expected to be a novel therapeutic target for the treatment of Alzheimer's disease.

Keywords: Alzheimer's disease; I2PP2A; neurofibrillary tangle; protein phosphatase 2A; tau

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1479-8301.2009.00289.x

Affiliations: 1: Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan, and 2: Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA

Publication date: 2009-06-01