Substrate-specific reduction of PP2A activity exaggerates tau pathology

Deters, Natasha, Ittner, Lars M. and Gotz, Jurgen (2009) Substrate-specific reduction of PP2A activity exaggerates tau pathology. Biochemical and Biophysical Research Communications, 379 2: 400-405. doi:10.1016/j.bbrc.2008.12.140


Author Deters, Natasha
Ittner, Lars M.
Gotz, Jurgen
Title Substrate-specific reduction of PP2A activity exaggerates tau pathology
Journal name Biochemical and Biophysical Research Communications   Check publisher's open access policy
ISSN 0006-291X
1090-2104
Publication date 2009-02-06
Sub-type Article (original research)
DOI 10.1016/j.bbrc.2008.12.140
Open Access Status
Volume 379
Issue 2
Start page 400
End page 405
Total pages 6
Place of publication Philadelphia, PA, United States
Publisher Elsevier
Language eng
Abstract Phosphorylation of the microtubule-associated protein tau is regulated by the balanced interplay of kinases and phosphatases. Disturbance of this balance causes hyperphosphorylation of tau and neurofibrillary tangle formation in Alzheimer's disease brain. Here, we crossed Dom5 mice that express a substrate-specific dominant negative mutant form, L309A Cα, of protein phosphatase 2A (PP2A) with neurofibrillary-tangle-forming P301L mutant tau transgenic pR5 mice. This exacerbated the tau pathology of pR5 mice significantly. Double-transgenic Dom5/pR5 mice showed 7-fold increased numbers of hippocampal neurons that specifically phosphorylated the pathological S422 epitope of tau. They showed 8-fold increased numbers of tangles compared to pR5 mice, in agreement with our previous finding that tangle formation is correlated with and preceded by phosphorylation of tau at the S422 epitope. This suggests that, in addition to kinases, PP2A and its regulatory subunits may be a therapeutic target for Alzheimer's disease.
Keyword Alzheimer's disease (AD)
Frontotemporal dementia (FTD)
Kinase
Microtubule
Neurofibrillary tangle (NFT)
Phosphatase
Tau
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
 
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