The DOI matches its Crossref record; 56 of the 56 references it cites were found in a registry or an index.
Mice lacking phosphatase PP2A subunit PR61/B’δ ( Ppp2r5d ) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3β
Open accessAbstract
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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IDENTIFICATION AND CHARACTERIZATION OF CIP2A AS A NOVEL ONCOGENIC INHIBITOR OF PP2A
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THE ROLE OF MICROTUBULE-ASSOCIATED PROTEIN TAU IN NEURONAL EXCITABILITY AND EPILEPTOGENESIS
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A girl with a de novo PPP2R5D W207R pathogenic variant was also born with an occipital encephalocele
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Metadata
- Authors
- Louis, J. V., Martens, E., Borghgraef, P., Lambrecht, C., Sents, W., Longin, S., Zwaenepoel, K., Pijnenborg, R., Landrieu, I., Lippens, G., Ledermann, B., Götz, J., Van Leuven, F., Goris, J., & Janssens, V.
- Affiliations
- KU Leuven (BE)
- Centre National de la Recherche Scientifique (FR)
- Novartis (Switzerland) (CH)
- The University of Sydney (AU)
- Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit, Leuven, Belgium;
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-04-11
- Volume
- 108
- Issue
- 17
- Pages
- 6957-6962
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3084077
- OpenAlex
- W2084623733
- Cited by
- 112
- References
- 56
- Citations by year
- 2025: 5 · 2024: 4 · 2023: 8 · 2022: 6 · 2021: 13 · 2020: 13 · 2019: 7 · 2018: 4 · 2017: 11 · 2016: 3 · 2015: 10 · 2014: 8 · 2013: 8 · 2012: 9
- FWCI
- 6.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion, other-oa)
- HAL (submittedVersion)
- Funders
- Vlaamse regering
- Medical Research Council
- National Health and Medical Research Council
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- protein phosphatase 2A, PPP2R5D, tauopathy, tau phosphorylation, cyclin-dependent kinase 5, p35, glycogen synthase kinase-3β, tau dephosphorylation, tau overexpression, neurofibrillary tangles, sensorimotor behavior, tau conformation, mouse knockout
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Brain, Nerve Tissue Proteins, Phosphorylation, PC12 Cells, tau Proteins, Protein Folding, Mice, Knockout, Tauopathies, Glycogen Synthase Kinase 3, Cyclin-Dependent Kinase 5, Mice, Rats, Protein Phosphatase 2
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