Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Loopholes in the DNA contract kill neurons

Hexanucleotide repeat expansions in C9orf72 gene locus create double jeopardy, first by leading to DNA–RNA R-loops that spawn double-strand breaks and second by the synthesis of dipeptide repeats that hinder DNA repair. This two-pronged mechanism may explain neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: The complex pathways from C9orf72 repeats to neuronal death.


  1. McKinnon, P.J. Nat. Neurosci. 16, 1523–1529 (2013).

    Article  CAS  Google Scholar 

  2. Walker, C. et al. Nat. Neurosci. 20, 1225–1235 (2017).

    Article  CAS  Google Scholar 

  3. Flores, B.N. et al. PLoS One 11, e0165084 (2016).

    Article  Google Scholar 

  4. Zhang, Y.J. et al. Acta Neuropathol. 128, 505–524 (2014).

    Article  CAS  Google Scholar 

  5. May, S. et al. Acta Neuropathol. 128, 485–503 (2014).

    Article  CAS  Google Scholar 

  6. Li, J. et al. Nat. Neurosci. 16, 1745–1753 (2013).

    Article  Google Scholar 

  7. Goodarzi, A.A., Noon, A.T. & Jeggo, P.A. Biochem. Soc. Trans. 37, 569–576 (2009).

    Article  CAS  Google Scholar 

  8. Aoki, Y. et al. Brain 140, 887–897 (2017).

    Article  Google Scholar 

  9. Boeynaems, S. et al. Mol. Cell 65, 1044–1055.e5 (2017).

    Article  CAS  Google Scholar 

  10. Schmidt, M.H. & Pearson, C.E. DNA Repair (Amst.) 38, 117–126 (2016).

    Article  CAS  Google Scholar 

  11. Kobayashi, H. et al. Am. J. Hum. Genet. 89, 121–130 (2011).

    Article  CAS  Google Scholar 

  12. Chow, H.M. & Herrup, K. Nat. Rev. Neurosci. 16, 672–684 (2015).

    Article  CAS  Google Scholar 

  13. Tse, K.H. & Herrup, K. Mech. Ageing Dev. 161 Pt A, 37–50 (2017).

    Article  Google Scholar 

  14. Suberbielle, E. et al. Nat. Neurosci. 16, 613–621 (2013).

    Article  CAS  Google Scholar 

  15. Shen, X., Chen, J., Li, J., Kofler, J. & Herrup, K. eNeuro (2016).

    Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Karl Herrup, Kai-Hei Tse or Hei-Man Chow.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Herrup, K., Tse, KH. & Chow, HM. Loopholes in the DNA contract kill neurons. Nat Neurosci 20, 1192–1194 (2017).

Download citation

  • Published:

  • Issue Date:

  • DOI:


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing