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Title: Mice lacking phosphatase PP2A subunit PR61/B'{delta} (Ppp2r5d) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3{beta}
Authors: Louis, Justin Vijay *
Martens, Ellen *
Borghgraef, Peter
Lambrecht, Caroline
Sents, Ward
Longin, Sari
Zwaenepoel, Karen
Pijnenborg, Robert
Landrieu, Isabelle
Lippens, Guy
Ledermann, Birgit
Götz, Jürgen
Van Leuven, Fred
Goris, Jozef
Janssens, Veerle # ×
Issue Date: Apr-2011
Publisher: National Academy of Sciences
Series Title: Proceedings of the National Academy of Sciences of the United States of America vol:108 issue:17 pages:6957-6962
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 (PP2A(T61δ)) 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 PP2A(T61δ) 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.
URI: 
ISSN: 0027-8424
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Faculty of Pharmaceutical Sciences - miscellaneous
Laboratory of Protein Phosphorylation and Proteomics
Laboratory of Experimental Genetics and Transgenesis (-)
Biochemistry Section (Medicine) (-)
Section Woman - Miscellaneous (-)
Department of Human Genetics - miscellaneous
* (joint) first author
× corresponding author
# (joint) last author

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