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Epigenetic Blockade of Hippocampal SOD2 Via DNMT3b-Mediated DNA Methylation: Implications in Mild Traumatic Brain Injury-Induced Persistent Oxidative Damage

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Abstract

The recurrent events of mild trauma exacerbate the vulnerability for post-traumatic stress disorder; however, the underlying molecular mechanisms are scarcely known. The repeated mild traumatic brain injury (rMTBI) perturbs redox homeostasis which is primarily managed by superoxide dismutase 2 (SOD2). The current study investigates the role of DNA methylation in SOD2 gene regulation and its involvement in rMTBI-induced persistent neuropathology inflicted by weight drop injury paradigm. The oxidative damage, neurodegenerative indicators, and SOD2 function and its regulation in the hippocampus were analyzed after 48 h and 30 days of rMTBI. The temporal and episodic increase in ROS levels (oxidative stress) heightened 8-hydroxyguanosine levels indicating oxidative damage after rMTBI that was concomitant with decline in SOD2 function. In parallel, occupancy of DNMT3b at SOD2 promoter was higher post 30 days of the first episode of rMTBI causing hypermethylation at SOD2 promoter. This epigenetic silencing of SOD2 promoter was sustained after the second episode of rMTBI causing permanent blockade in SOD2 response. The resultant oxidative stress further culminated into the increasing number of degenerating neurons. The treatment with 5-azacytidine, a pan DNMT inhibitor, normalized DNA methylation levels and revived SOD2 function after the second episode of rMTBI. The release of blockade in SOD2 expression by DNMT inhibition also normalized the post-traumatic oxidative consequences and relieved the neurodegeneration and deficits in learning and memory as measured by novel object recognition test. In conclusion, DNMT3b-mediated DNA methylation plays a critical role in SOD2 gene regulation in the hippocampus, and the perturbations therein post rMTBI are detrimental to redox homeostasis manifesting into neurological consequences.

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  • 11 November 2020

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Acknowledgments

The authors kindly acknowledge Dr. Chaitanya Athale, Indian Institute of Science Education and Research-Pune (IISER-Pune), India, for the generous gift of PC12 cell line cultures and Institute for Applied Biological Research and Development (IABRD), Pune, for their technical support in in vitro experiments.

Funding

This work was supported by the grants from the University Grants Commission, Government of India (UGC-GOI; F.4-5/151-FRP/2014/BSR); Science and Engineering Research Board (SERB), GOI (EMR/2017/000621); and Council for Scientific and Industrial Research (CSIR), GOI (37[1718]/18/EMR-II) to AJS. AJS also acknowledges funds received through the Department Research and Development Program of the Department of Biotechnology, Savitribai Phule Pune University, Pune, India. NB thanks the UGC-GOI for the award of Senior Research Fellowship (File No. 2061330923). SS acknowledges DST INSPIRE-Faculty program (DST/INSPIRE/04/2018/000529) for the funding support. DMK acknowledges the grants from the University Research Project Scheme (URPS; Dev./RTMNURP/AH/2115) from Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur.

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Authors and Affiliations

  1. Department of Biotechnology, Savitribai Phule Pune University, Pune, 411 007, India

    Nagalakshmi Balasubramanian, Sneha Sagarkar & Amul J. Sakharkar

  2. Department of Zoology, Savitribai Phule Pune University, Pune, 411 007, India

    Sneha Sagarkar

  3. Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, 440 033, India

    Amit G. Choudhary & Dadasaheb M. Kokare

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  1. Nagalakshmi Balasubramanian
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Correspondence to Amul J. Sakharkar.

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Balasubramanian, N., Sagarkar, S., Choudhary, A.G. et al. Epigenetic Blockade of Hippocampal SOD2 Via DNMT3b-Mediated DNA Methylation: Implications in Mild Traumatic Brain Injury-Induced Persistent Oxidative Damage. Mol Neurobiol 58, 1162–1184 (2021). https://doi.org/10.1007/s12035-020-02166-z

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