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Increased DNA Damage and Apoptosis in CDKL5-Deficient Neurons

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A Correction to this article was published on 17 February 2020

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Abstract

Mutations in the CDKL5 gene, which encodes a serine/threonine kinase, causes a rare encephalopathy, characterized by early-onset epilepsy and severe intellectual disability, named CDKL5 deficiency disorder (CDD). In vitro and in vivo studies in mouse models of Cdkl5 deficiency have highlighted the role of CDKL5 in brain development and, in particular, in the morphogenesis and synaptic connectivity of hippocampal and cortical neurons. Interestingly, Cdkl5 deficiency in mice increases vulnerability to excitotoxic stress in hippocampal neurons. However, the mechanism by which CDKL5 controls neuronal survival is far from being understood. To investigate further the function of CDKL5 and dissect the molecular mechanisms underlying neuronal survival, we generated a human neuronal model of CDKL5 deficiency, using CRISPR/Cas9-mediated genome editing. We demonstrated that CDKL5 deletion in human neuroblastoma SH-SY5Y cells not only impairs neuronal maturation but also reduces cell proliferation and survival, with alterations in the AKT and ERK signaling pathways and an increase in the proapoptotic BAX protein and in DNA damage-associated biomarkers (i.e., γH2AX, RAD50, and PARP1). Furthermore, CDKL5-deficient cells were hypersensitive to DNA damage-associated stress, accumulated more DNA damage foci (γH2AX positive) and were more prone to cell death than the controls. Importantly, increased kainic acid-induced cell death of hippocampal neurons of Cdkl5 KO mice correlated with an increased γH2AX immunostaining. The results suggest a previously unknown role for CDKL5 in DNA damage response that could underlie the pro-survival function of CDKL5.

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  • 17 February 2020

    The original version of this article unfortunately contained error in Fig. 5a to where a panel is missing.

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Acknowledgments

This work was supported by the Italian parent association “CDKL5 insieme verso la cura.”

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  1. Manuela Loi and Stefania Trazzi contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical and Neuromotor Sciences, University of Bologna, Piazza di Porta San Donato 2, 40126, Bologna, Italy

    Manuela Loi, Stefania Trazzi, Claudia Fuchs, Giuseppe Galvani, Giorgio Medici, Laura Gennaccaro, Marianna Tassinari & Elisabetta Ciani

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Loi, M., Trazzi, S., Fuchs, C. et al. Increased DNA Damage and Apoptosis in CDKL5-Deficient Neurons. Mol Neurobiol 57, 2244–2262 (2020). https://doi.org/10.1007/s12035-020-01884-8

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