Mice lacking phosphatase PP2A subunit PR61/B' (Ppp2r5d) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3

Louis, J. V. and Martens, E. and Borghgraef, P. and Lambrecht, C. and Sents, W. and Longin, S. and Zwaenepoel, K. and Pijnenborg, R. and Landrieu, I. and Lippens, G. and Ledermann, B. and Gotz, J. and Van Leuven, F. and Goris, J. and Janssens, V. (2011) Mice lacking phosphatase PP2A subunit PR61/B' (Ppp2r5d) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3. Proceedings of the National Academy of Sciences, 108 (17). pp. 6957-6962. ISSN 0027-8424


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Official URL: http://dx.doi.org/10.1073/pnas.1018777108


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 PP2AT61δ 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.

Item Type: Article
Subjects: Pharmaceutical Sciences
Divisions: College of Pharmacy > Pharmaceutical Sciences
Depositing User: Dr Justin Louis
Date Deposited: 14 Jun 2017 10:50
Last Modified: 14 Jun 2017 10:50
URI: http://eprints.kku.edu.sa/id/eprint/759

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