ArticleProceedings of the National Academy of Sciences of the United States of America2011
Mice lacking phosphatase PP2A subunit PR61/B'delta (Ppp2r5d) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3beta.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers.
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Who cites it
69 citing papers in PubMed, 115 citations in OpenAlex.
- PP2A methylesterase, PME-1, and PP2A methyltransferase, LCMT-1, control sensitivity to impairments caused by injury-related oligomeric tau.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Targeting PP2A in cancer: an underrated option.Journal of experimental & clinical cancer research : CR · 2025Review
- Houge-Janssens syndrome.European journal of human genetics : EJHG · 2025Review
- Pathogenic de novo variants in PPP2R5C cause a neurodevelopmental disorder within the Houge-Janssens syndrome spectrum.American journal of human genetics · 2025Article
- Saturated fatty acids stimulate cytokine production in tanycytes via the PP2Ac-dependent signaling pathway.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2024Article
- Article
- A Novel Mouse Model of Combined Hepatocellular-Cholangiocarcinoma Induced by Diethylnitrosamine and Loss ofCancers · 2023Article
- The Deficits of Insulin Signal in Alzheimer's Disease and the Mechanisms of Vanadium Compounds in Curing AD.Current issues in molecular biology · 2023Review
- Protein Phosphatase 2A Regulates Phenotypic and Metabolic Alteration of Microglia Cells in HFD-Associated Vascular Dementia Mice via TNF-α/Arg-1 Axis.Molecular neurobiology · 2023Article
- Review
- Anesthesia promotes acute expression of genes related to Alzheimer's disease and latent tau aggregation in transgenic mouse models of tauopathy.Molecular medicine (Cambridge, Mass.) · 2022Article
- Growth arrest of PPP2R5C and PPP2R5D double knockout mice indicates a genetic interaction and conserved function for these PP2A B subunits.FASEB bioAdvances · 2022Article
- Amyloid-like aggregating proteins cause lysosomal defects in neurons via gain-of-function toxicity.Life science alliance · 2022Article
- The role of serine/threonine phosphatases in human development: Evidence from congenital disorders.Frontiers in cell and developmental biology · 2022Review
- Modulation of Phosphoprotein Activity by Phosphorylation Targeting Chimeras (PhosTACs).ACS chemical biology · 2021Article
- Refractory Epilepsy in a Toddler With PPP2R1A Gene Mutation and Congenital Hydrocephalus.Cureus · 2021Article
- The B56α subunit of PP2A is necessary for mesenchymal stem cell commitment to adipocyte.EMBO reports · 2021Article
- Protein phosphatase 2A - structure, function and role in neurodevelopmental disorders.Journal of cell science · 2021Review
- Deferiprone Treatment in Aged Transgenic Tau Mice Improves Y-Maze Performance and Alters Tau Pathology.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021Article
- Altered Cerebrospinal Fluid Exosomal microRNA Levels in Young-Onset Alzheimer's Disease and Frontotemporal Dementia.Journal of Alzheimer's disease reports · 2021Article
9 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 4 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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