P3–329: I1PP2A and I2PP2A affect tau phosphorylation via association with the catalytic subunit of protein phosphatase 2A
Year: 2006
Type: article
Abstract: Decreased protein phosphatase–2A (PP–2A) is believed to be a cause of neurofibrillary degeneration of abnormally hyperphosphorylated tau in Alzheimer disease (AD). The activity of PP–2A is regulated by two potent PP–2A inhibitor proteins, I1 and I2. To investigate whether I1 and I2 can inhibit PP–2A activity via direct interaction with PP–2A, the minimal domains required for the association, and how the interaction affects tau phosphorylation at particular sites. Inhibition of PP–2A activity was detected in I1 and I2 transiently transfected NIH3T3 cells. Interaction between PP–2A and I1 or I2 was determined by GST–pull down assay, and further confirmed by co–localization in cultured cells, PP–2A overlay assay, and by in vitro co–immunoprecipitation. A series of deletion mutants of I1 or I2 were employed to pinpoint the minimal region required for the interaction. Tau phosphorylation status at different sites was determined by Western blots of inhibitor –transfected and, as control, mock–transfected cells. We found that I1 can reduce PP–2A activity to ∼56%, whereas I2 can inhibit PP–2A activity to ∼67% in NIH3T3 cells. I1 and I2 can interact with PP–2Ac (PP–2A catalytic subunit), however, no associations between I1 or I2 and PR65α (PP–2A A regulatory subunit) or PR55α (PP–2A Bα regulatory subunit) were observed. The minimal domain required for interaction with PP–2Ac is located at the N–terminal part of I1, whereas it resides at the C–terminal of I2. I1 and I2inhibit PP–2A activity by interacting with its catalytic subunit (PP–2Ac) but not its regulatory subunits A or Bα. The interactions of the inhibitors with PP–2Ac appear to be relatively weak.
Source: Alzheimer s & Dementia
Authors: She Chen, Inge Grundke-Iqbal, Khalid Iqbal
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W3021703201