title: Genetic ablation of homeodomain-interacting protein kinase 2 selectively induces apoptosis of cerebellar Purkinje cells during adulthood and generates an ataxic-like phenotype.
abstract: Homeodomain-interacting protein kinase 2 (HIPK2) is a multitalented coregulator of an increasing number of transcription factors and cofactors involved in cell death and proliferation in several organs and systems. As Hipk2(-/-) mice show behavioral abnormalities consistent with cerebellar dysfunction, we investigated whether Hipk2 is involved in these neurological symptoms. To this aim, we characterized the postnatal developmental expression profile of Hipk2 in the brain cortex, hippocampus, striatum, and cerebellum of mice by real-time PCR, western blot analysis, and immunohistochemistry. Notably, we found that whereas in the brain cortex, hippocampus, and striatum, HIPK2 expression progressively decreased with age, that is, from postnatal day 1 to adulthood, it increased in the cerebellum. Interestingly, mice lacking Hipk2 displayed atrophic lobules and a visibly smaller cerebellum than did wild-type mice. More important, the cerebellum of Hipk2(-/-) mice showed a strong reduction in cerebellar Purkinje neurons during adulthood. Such reduction is due to the activation of an apoptotic process associated with a compromised proteasomal function followed by an unpredicted accumulation of ubiquitinated proteins. In particular, Purkinje cell dysfunction was characterized by a strong accumulation of ubiquitinated β-catenin. Moreover, our behavioral tests showed that Hipk2(-/-) mice displayed muscle and balance impairment, indicative of Hipk2 involvement in cerebellar function. Taken together, these results indicate that Hipk2 exerts a relevant role in the survival of cerebellar Purkinje cells and that Hipk2 genetic ablation generates cerebellar dysfunction compatible with an ataxic-like phenotype.
authors.affiliation: SDN IRCCS, Naples, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Anzilotti
authors.affiliation: Institute of Endocrinology and Experimental Oncology of National Research Council and Department of Molecular Medicine and Medical Biotechnology, School of Medicine, 'Federico II' University of Naples, Naples, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Tornincasa
authors.affiliation: Institute of Endocrinology and Experimental Oncology of National Research Council and Department of Molecular Medicine and Medical Biotechnology, School of Medicine, 'Federico II' University of Naples, Naples, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Gerlini
authors.affiliation: Institute of Endocrinology and Experimental Oncology of National Research Council and Department of Molecular Medicine and Medical Biotechnology, School of Medicine, 'Federico II' University of Naples, Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Conte
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, 'Federico II' University of Naples, Naples, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Brancaccio
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, 'Federico II' University of Naples, Naples, Italy.
authors.forename: O
authors.initials: O
authors.lastname: Cuomo
authors.affiliation: Institute of Endocrinology and Experimental Oncology of National Research Council and Department of Molecular Medicine and Medical Biotechnology, School of Medicine, 'Federico II' University of Naples, Naples, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Bianco
authors.affiliation: Institute of Endocrinology and Experimental Oncology of National Research Council and Department of Molecular Medicine and Medical Biotechnology, School of Medicine, 'Federico II' University of Naples, Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Fusco
authors.affiliation: SDN IRCCS, Naples, Italy.|Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, 'Federico II' University of Naples, Naples, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Annunziato
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, 'Federico II' University of Naples, Naples, Italy.
authors.forename: G
authors.identifier: http://orcid.org/0000-0002-7290-4397
authors.initials: G
authors.lastname: Pignataro
authors.affiliation: Institute of Endocrinology and Experimental Oncology of National Research Council and Department of Molecular Medicine and Medical Biotechnology, School of Medicine, 'Federico II' University of Naples, Naples, Italy.
authors.forename: G M
authors.initials: GM
authors.lastname: Pierantoni
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011689:Purkinje Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D051176:beta Catenin; C115114:HIPK2 protein, human; C492003:Hipk2 protein, mouse; D017346:Protein Serine-Threonine Kinases