Acetyltransferases (HATs) as Targets for Neurological Therapeutics

Abstract

The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen long-term events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

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Acknowledgments

This work was supported by funding from the Centre National de la Recherche Scientifique (CNRS), the University of Strasbourg, the Department of Biotechnology, the Government of India (Grant/ DBT/ CSH/ GIA/ 1752 to TKK), the Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Agence Nationale de la Recherche (ANR-12-MALZ-0002-01 to ALB), the Indo-French Centre for the Promotion of Advanced Research (IFCPAR/CEFIPRA No.4803-3 to T.K. Kundu and A.L. Boutillier), and Alsace Alzheimer 67 association (to A.L. Boutillier and F. Blanc). T.K. Kundu is a recipient of the Sir JC Bose national fellowship from the Department of Science and Technology through the government of India. Raphaelle Cassel received a doctoral fellowship from the French government. A. Schneider was supported through the Agence Nationale pour la Recherche (ANR-12-MALZ-0002). Frédéric Blanc reports receiving personal fees from Eisai, Piramal, Biogen Novartis, Janssen, Lundbeck, Pfizer, and Biogen, and non-financial support from Novartis, Lundbeck, Bayer Schering, Merck Serono, TEVA Neurosciences, and Pfizer, outside of the submitted work. Amrutha Swaminathan reports receiving grants from the Council for Scientific and Industrial Research, outside of the submitted work. Anne L. Boutillier, S. Chatterjee, and T.K. Kundu have a patent HAT Activator CSP-TTK21 pending. Olivier Bousiges, R. Cassel, A. Schneider, and B.R. Selvi. have nothing to disclose.

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Schneider, A., Chatterjee, S., Bousiges, O. et al. Acetyltransferases (HATs) as Targets for Neurological Therapeutics. Neurotherapeutics 10, 568–588 (2013). https://doi.org/10.1007/s13311-013-0204-7

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Keywords

  • HAT activator molecule
  • Lysine acetylation
  • CREB-binding protein
  • Learning and memory
  • Adult neurogenesis
  • Neurodegenerative diseases