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In vivo delivery of DN:REST improves transcriptional changes of REST-regulated genes in HD mice

Gene Therapy volume 20, pages 678–685 (2013)Cite this article

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Abstract

Current therapeutic strategies for Huntington’s disease (HD) are focused on symptom management of disease progression. Transcriptional dysregulation is one of the major characteristics in HD. REST is a transcriptional repressor that silences gene expression through binding to RE1/NRSE sites found in the regulatory regions of numerous neuronal genes. Dysregulation of REST and its targeted genes has been reported in different cell and mouse HD models, as well as in biopsies from human patients. In this work, we characterized transcriptional dysregulation associated with REST in two different HD mouse models and assessed the therapeutic effect of interfering with REST function by overexpressing a dominant-negative form (DN:REST). We show that delivery of DN:REST in the motor cortex restores brain-derived neurotrophic factor (BDNF) mRNA and protein levels by reducing endogenous REST occupancy at the Bdnf locus. Similarly, expression of other REST-regulated genes such as Synapsin I (Syn1), Proenkephalin (Penk1) and Cholinergic receptor muscarinic 4 (Chrm4) were restored to normal levels while non-REST-regulated genes were unaffected. This is the first study conducted to investigate REST’s role in vivo in a neurodegenerative disease. Our data show that DN:REST in motor cortex reversed RESTs repressive effects on target genes. However, the lack of therapeutic effect on motor function suggests that a more widespread rescue of REST-regulated sites in the affected brain regions may be necessary.

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Acknowledgements

This research was supported by CHDI Foundation (NY, USA) to EC, NB and BD, by Ministero dell’Istruzione dell’Università e della Ricerca (MIUR, 2008 JKSHKN) and, partially, by Fondazione Cariplo (Italy) to EC and the Roy J Carver Trust to BD.

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  1. P Conforti and A Mas Monteys: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Stem Cell Research, Università degli Studi di Milano, Milan, Italy

    P Conforti, C Zuccato & E Cattaneo

  2. Department of Internal Medicine, University of Iowa, Iowa City, IA, USA

    A Mas Monteys & B Davidson

  3. King’s College London, Institute of Psychiatry, Centre for the Cellular Basis of Behavior, London, UK

    N J Buckley

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  1. P Conforti
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  2. A Mas Monteys
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Correspondence to E Cattaneo.

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Conforti, P., Mas Monteys, A., Zuccato, C. et al. In vivo delivery of DN:REST improves transcriptional changes of REST-regulated genes in HD mice. Gene Ther 20, 678–685 (2013). https://doi.org/10.1038/gt.2012.84

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