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Modulation of Synaptic Plasticity Genes Associated to DNA Damage in a Model of Huntington’s Disease

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Abstract

Huntington’s disease (HD) is a disease characterized by the progressive degeneration of nerve cells in the brain. DNA damage has been implicated in many neurological disorders; however, the association between this damage and the impaired signaling related to neurodegeneration is still unclear. The transcription factor c-AMP-responsive element binding protein (CREB) has a relevant role in the neuronal plasticity process regulating the expression of several genes, including brain-derived neurotrophic factor (BDNF). Here we analyzed the direct link between DNA damage and the expression of genes involved in neuronal plasticity. The study was performed in model cell lines STHdhQ7 (wild type) and STHdhQ111 (HD model). Treatment with Etoposide (Eto) was used to induce double-strand breaks (DSBs) to evaluate the DNA damage response (DDR) and the expression of synaptic plasticity genes. Eto treatment induced phosphorylation of ATM (p-ATM) and H2AX (γH2AX), markers of DDR, in both cell lines. Interestingly, upon DNA damage, STHdhQ7 cells showed increased expression of activity-regulated cytoskeleton associated protein (Arc) and BDNF when compared to the HD cell line model. Additionally, Eto induced CREB activation with a differential localization of its co-activators in the cell types analyzed. These results suggest that DSBs impact differentially the gene expression patterns of plasticity genes in the normal cell line versus the HD model. This effect is mediated by the impaired localization of CREB-binding protein (CBP) and histone acetylation in the HD model. Our results highlight the role of epigenetics and DNA repair on HD and therefore we suggest that future studies should explore in depth the epigenetic landscape on neuronal pathologies with the goal to further understand molecular mechanisms and pinpoint therapeutic targets.

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Data Availability

The datasets generated during and/or analyzed during the current study are available by request; please contact the corresponding author.

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Acknowledgements

We thank Francisco J. Morera, Ph.D., from Universidad Austral de Chile, for the helpful discussions of the results. We thank Claudia A. Tapia-Alveal, PhD., from Columbia University New York, U.S.A., for her critical reading of the manuscript.

Funding

This work was supported by grants FONDECYT REGULAR 1141067 (to A.Z.) and 1191620 (M.A.C), and VIDCA from Universidad Austral de Chile.

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Authors and Affiliations

  1. Facultad de Ciencias, Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Casilla (P. O. Box) 567, Valdivia, Chile

    Johana Spies, Adriana Covarrubias-Pinto, Constanza Carcamo, Yennyfer Arancibia, Fernanda Salazar, Carolina Paredes-Martinez, Maite Castro & Angara Zambrano

  2. Facultad de Medicina, Instituto de Microbiología Clínica, Universidad Austral de Chile, Valdivia, Chile

    Carola Otth

  3. Center for Interdisciplinary Studies on the Nervous System (CISNe), Universidad Austral de Chile, Valdivia, Chile

    Carolina Paredes-Martinez, Carola Otth, Maite Castro & Angara Zambrano

  4. Centro Interdisciplinario de Neurociencias de Valparaíso (CINV), Valparaíso, Chile

    Maite Castro

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Contributions

MC and AZ., conceived and designed the experiment; JS., AC., CC., CP-M. and AZ. performed experiments and acquired the data; JS., AC., MC., and AZ., analyzed and interpreted the data; FS., MC., CO., and AZ. drafted, edited, and revised manuscript.

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Correspondence to Angara Zambrano.

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The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

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Spies, J., Covarrubias-Pinto, A., Carcamo, C. et al. Modulation of Synaptic Plasticity Genes Associated to DNA Damage in a Model of Huntington’s Disease. Neurochem Res 48, 2093–2103 (2023). https://doi.org/10.1007/s11064-023-03889-w

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