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Shin B, Jung R, Oh H, et al. Novel DNA Aptamers that Bind to Mutant Huntingtin and Modify Its Activity. Mol Ther Nucleic Acids. 2018;11:416-428doi: 10.1016/j.omtn.2018.03.008.
Shin, B., Jung, R., Oh, H., Owens, G. E., Lee, H., Kwak, S., Lee, R., Cotman, S. L., Lee, J. M., MacDonald, M. E., Song, J. J., Vijayvargia, R., & Seong, I. S. (2018). Novel DNA Aptamers that Bind to Mutant Huntingtin and Modify Its Activity. Molecular therapy. Nucleic acids, 11416-428. https://doi.org/10.1016/j.omtn.2018.03.008
Shin, Baehyun, et al. "Novel DNA Aptamers that Bind to Mutant Huntingtin and Modify Its Activity." Molecular therapy. Nucleic acids vol. 11 (2018): 416-428. doi: https://doi.org/10.1016/j.omtn.2018.03.008
Shin B, Jung R, Oh H, Owens GE, Lee H, Kwak S, Lee R, Cotman SL, Lee JM, MacDonald ME, Song JJ, Vijayvargia R, Seong IS. Novel DNA Aptamers that Bind to Mutant Huntingtin and Modify Its Activity. Mol Ther Nucleic Acids. 2018 Jun 01;11:416-428. doi: 10.1016/j.omtn.2018.03.008. Epub 2018 Mar 16. PMID: 29858077; PMCID: PMC5992459.
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Mol Ther Nucleic Acids. 2018 Jun 01;11:416-428. doi: 10.1016/j.omtn.2018.03.008. Epub 2018 Mar 16.

Novel DNA Aptamers that Bind to Mutant Huntingtin and Modify Its Activity.

Molecular therapy. Nucleic acids

Baehyun Shin, Roy Jung, Hyejin Oh, Gwen E Owens, Hyeongseok Lee, Seung Kwak, Ramee Lee, Susan L Cotman, Jong-Min Lee, Marcy E MacDonald, Ji-Joon Song, Ravi Vijayvargia, Ihn Sik Seong

Affiliations

  1. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02114, USA.
  2. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
  3. Department of Biological Sciences, KAIST Institute for the BioCentury, Center for Cancer Metastasis, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
  4. CHDI Foundation, Princeton, NJ 08540, USA.
  5. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02114, USA. Electronic address: [email protected].
  6. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02114, USA. Electronic address: [email protected].

PMID: 29858077 PMCID: PMC5992459 DOI: 10.1016/j.omtn.2018.03.008

Abstract

The CAG repeat expansion that elongates the polyglutamine tract in huntingtin is the root genetic cause of Huntington's disease (HD), a debilitating neurodegenerative disorder. This seemingly slight change to the primary amino acid sequence alters the physical structure of the mutant protein and alters its activity. We have identified a set of G-quadruplex-forming DNA aptamers (MS1, MS2, MS3, MS4) that bind mutant huntingtin proximal to lysines K2932/K2934 in the C-terminal CTD-II domain. Aptamer binding to mutant huntingtin abrogated the enhanced polycomb repressive complex 2 (PRC2) stimulatory activity conferred by the expanded polyglutamine tract. In HD, but not normal, neuronal progenitor cells (NPCs), MS3 aptamer co-localized with endogenous mutant huntingtin and was associated with significantly decreased PRC2 activity. Furthermore, MS3 transfection protected HD NPCs against starvation-dependent stress with increased ATP. Therefore, DNA aptamers can preferentially target mutant huntingtin and modulate a gain of function endowed by the elongated polyglutamine segment. These mutant huntingtin binding aptamers provide novel molecular tools for delineating the effects of the HD mutation and encourage mutant huntingtin structure-based approaches to therapeutic development.

Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords: HEAT repeats; Huntington's disease; full-length huntingtin; polycomb repressive complex 2; single-stranded oligonucleotide

References

  1. Nat Genet. 1995 Oct;11(2):115-6 - PubMed
  2. Nat Neurosci. 2016 Oct;19(10 ):1321-30 - PubMed
  3. Hum Mol Genet. 2015 Jan 15;24(2):450-62 - PubMed
  4. Nucleic Acids Res. 2014 Apr;42(8):e65 - PubMed
  5. EMBO J. 2015 Feb 3;34(3):267-9 - PubMed
  6. Hum Mol Genet. 2017 Jan 15;26(2):395-406 - PubMed
  7. Hum Mol Genet. 2015 May 1;24(9):2442-57 - PubMed
  8. BMC Neurosci. 2002 Oct 14;3:15 - PubMed
  9. Anal Chem. 1996 Mar 1;68(5):850-8 - PubMed
  10. Nat Rev Drug Discov. 2010 Jul;9(7):537-50 - PubMed
  11. Nat Biotechnol. 2006 Oct;24(10):1285-92 - PubMed
  12. Nat Rev Genet. 2005 Oct;6(10):756-65 - PubMed
  13. PLoS One. 2011;6(10):e26203 - PubMed
  14. Elife. 2016 Mar 22;5:e11184 - PubMed
  15. Nat Genet. 1993 Aug;4(4):393-7 - PubMed
  16. Cell. 1993 Mar 26;72(6):971-83 - PubMed
  17. Neurology. 2012 Mar 6;78(10):690-5 - PubMed
  18. Biochemistry. 2013 Aug 20;52(33):5620-8 - PubMed
  19. Curr Med Chem. 2009;16(10):1248-65 - PubMed
  20. Hum Mol Genet. 2011 Jul 15;20(14 ):2846-60 - PubMed
  21. Mol Ther. 2015 Dec;23 (12 ):1912-26 - PubMed
  22. J Biol Chem. 2000 Jun 30;275(26):19831-8 - PubMed
  23. Expert Opin Investig Drugs. 2008 Jan;17(1):43-60 - PubMed
  24. Hum Mol Genet. 2005 Oct 1;14 (19):2871-80 - PubMed
  25. Protein Sci. 2010 Jul;19(7):1395-404 - PubMed
  26. J Neurosci Res. 2010 Feb 1;88(2):335-45 - PubMed
  27. Hum Mol Genet. 2010 Feb 15;19(4):573-83 - PubMed
  28. Proc Natl Acad Sci U S A. 2011 Mar 22;108(12 ):4788-93 - PubMed
  29. Nucleic Acids Res. 2015 Oct 15;43(18):8627-37 - PubMed
  30. Nat Rev Neurosci. 2000 Nov;1(2):109-15 - PubMed
  31. J Mass Spectrom. 2001 Oct;36(10):1083-91 - PubMed
  32. J Am Soc Mass Spectrom. 1994 Nov;5(11):976-89 - PubMed
  33. BMC Neurosci. 2006 Oct 02;7:65 - PubMed
  34. Free Radic Biol Med. 2013 Sep;62:102-10 - PubMed
  35. Int J Mol Sci. 2014 Sep 29;15(10):17493-517 - PubMed
  36. Cell Stem Cell. 2012 Aug 3;11(2):264-78 - PubMed

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