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

• DOI: 10.1073/pnas.1018777108
• Publication Date: 2011-04-12T10:00:50Z
• Authors: Justin V. Louis; Ellen Martens; Peter Borghgraef; Caroline Lambrecht; Ward Sents; Sari Longin; Karen Zwaenepoel; Robert Pijnenborg; Isabelle Landrieu; Guy Lippens; Birgit Ledermann; Jürgen Götz; Fred Van Leuven; Jozef Goris; Veerle Janssens
• Keywords: Cyclin-dependent kinase 5; Tauopathy; Hyperphosphorylation; Dephosphorylation

Functional diversity of protein phosphatase 2A (PP2A) enzymes mainly results from their association with distinct regulatory subunits. To analyze the functions one such holoenzyme in vivo, we generated mice lacking PR61/B’δ (B56δ), a subunit highly expressed neural tissues. In PR61/B’δ-null microtubule-associated tau becomes progressively phosphorylated at pathological epitopes restricted brain areas, marked immunoreactivity for misfolded MC1-conformation but without neurofibrillary tangle formation. Behavioral tests indicated impaired sensorimotor normal cognitive functions. These phenotypical characteristics were further underscored mildly overexpressing human tau. PR61/B’δ-containing PP2A (PP2A T 61 δ ) poorly dephosphorylates vitro, arguing against direct dephosphorylation defect. Rather, activity glycogen synthase kinase-3β, major kinase, was found increased, decreased phosphorylation Ser-9, putative cyclin-dependent kinase 5 (CDK5) target. Accordingly, CDK5 is decreased, and its cellular activator p35, strikingly absent affected areas. As opposed to tau, p35 an excellent substrate. Our data imply nonredundant function phospho-tau homeostasis via unexpected spatially mechanism preventing hyperphosphorylation subsequent degradation.