title: Mice lacking phosphatase PP2A subunit PR61/B'delta (Ppp2r5d) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3beta.
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.
authors.affiliation: Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven, Belgium.
authors.forename: Justin V
authors.initials: JV
authors.lastname: Louis
authors.forename: Ellen
authors.initials: E
authors.lastname: Martens
authors.forename: Peter
authors.initials: P
authors.lastname: Borghgraef
authors.forename: Caroline
authors.initials: C
authors.lastname: Lambrecht
authors.forename: Ward
authors.initials: W
authors.lastname: Sents
authors.forename: Sari
authors.initials: S
authors.lastname: Longin
authors.forename: Karen
authors.initials: K
authors.lastname: Zwaenepoel
authors.forename: Robert
authors.initials: R
authors.lastname: Pijnenborg
authors.forename: Isabelle
authors.initials: I
authors.lastname: Landrieu
authors.forename: Guy
authors.initials: G
authors.lastname: Lippens
authors.forename: Birgit
authors.initials: B
authors.lastname: Ledermann
authors.forename: Jürgen
authors.initials: J
authors.lastname: Götz
authors.forename: Fred
authors.initials: F
authors.lastname: Van Leuven
authors.forename: Jozef
authors.initials: J
authors.lastname: Goris
authors.forename: Veerle
authors.initials: V
authors.lastname: Janssens
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology*; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation / Q000235:genetics; D017510:Protein Folding; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D024801:Tauopathies / Q000201:enzymology* / Q000235:genetics; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C489131:Mapt protein, rat; D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; C495906:Cdk5 protein, mouse; C495907:Cdk5 protein, rat; D038362:Glycogen Synthase Kinase 3; C475028:Ppp2r5d protein, mouse; D054648:Protein Phosphatase 2