Mice lacking phosphatase PP2A subunit PR61/B′δ (Ppp2r5d) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3β

Louis, Justin V., Martens, Ellen, Borghgraef, Peter, Lambrecht, Caroline, Sents, Ward, Longin, Sari, Zwaenepoel, Karen, Pijnenborg, Robert, Landrieu, Isabelle, Lippens, Guy, Ledermann, Birgit, Gotz, Jürgen, Van Leuven, Fred, Goris, Jozef and Janssens, Veerle (2011) Mice lacking phosphatase PP2A subunit PR61/B′δ (Ppp2r5d) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3β. Proceedings of the National Academy of Sciences of the United States of America, 108 17: 6957-6962. doi:10.1073/pnas.1018777108


Author Louis, Justin V.
Martens, Ellen
Borghgraef, Peter
Lambrecht, Caroline
Sents, Ward
Longin, Sari
Zwaenepoel, Karen
Pijnenborg, Robert
Landrieu, Isabelle
Lippens, Guy
Ledermann, Birgit
Gotz, Jürgen
Van Leuven, Fred
Goris, Jozef
Janssens, Veerle
Title Mice lacking phosphatase PP2A subunit PR61/B′δ (Ppp2r5d) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3β
Journal name Proceedings of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2011-04-26
Year available 2011
Sub-type Article (original research)
DOI 10.1073/pnas.1018777108
Open Access Status Not Open Access
Volume 108
Issue 17
Start page 6957
End page 6962
Total pages 6
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Formatted abstract
Functional diversity of protein phosphatase 2A (PP2A) enzymes mainly results from their association with distinct regulatory subunits. To analyze the functions of one such holoenzyme in vivo, we generated mice lacking PR61/B′δ (B56δ), a subunit highly expressed in neural tissues. In PR61/B′δ-null mice the microtubule-associated protein tau becomes progressively phosphorylated at pathological epitopes in restricted brain areas, with marked immunoreactivity for the misfolded MC1-conformation but without neurofibrillary tangle formation. Behavioral tests indicated impaired sensorimotor but normal cognitive functions. These phenotypical characteristics were further underscored in PR61/B′δ-null mice mildly overexpressing human tau. PR61/B′δ-containing PP2A (PP2AT61δ) poorly dephosphorylates tau in vitro, arguing against a direct dephosphorylation defect. Rather, the activity of glycogen synthase kinase-3β, a major tau kinase, was found increased, with decreased phosphorylation of Ser-9, a putative cyclin-dependent kinase 5 (CDK5) target. Accordingly, CDK5 activity is decreased, and its cellular activator p35, strikingly absent in the affected brain areas. As opposed to tau, p35 is an excellent PP2AT61β substrate. Our data imply a nonredundant function for PR61/B′δ in phospho-tau homeostasis via an unexpected spatially restricted mechanism preventing p35 hyperphosphorylation and its subsequent degradation. 
Keyword AT180
AT8
Brain stem
Knockout mouse
Transgenic
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID GOA/2008/16
IAP P6/28
G.0529.06
Institutional Status Non-UQ

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