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

摘要

Functional diversity of protein phosphatase 2A (PP2A) enzymes mainly results from their association with distinct regulatory sub-units. 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'8-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'8-null mice mildly overexpres-sing human tau. PR61/B'S-containing PP2A (PP2A_(761δ)) poorly dephosphorylates tau in vitro, arguing against a direct dephosph-orylation 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'8 in phospho-tau homeostasis via an unexpected spatially restricted mechanism preventing p35 hyperphosphorylation and its subsequent degradation.