New study on C9ORF72 and how it might cause FTD and motor neurone disease

An abnormality in the C9ORF72 gene is a common cause of both FTD and motor neurone disease. Recent work published in the journal Nature sheds new light on the way that C9ORF72 mutations cause these diseases.

The abnormality in the C9ORF72 gene that causes both FTD and MND is what is called an expansion. This is an abnormal part of a gene where there are extra letters inserted in the code. In C9ORF72 there is a hexanucleotide expansion, meaning that six letters are repeated multiple times. The six letters are GGGGCC and can be repeated over a thousand times in people with FTD compared to less than thirty in people without FTD.

Our genes form a code for the production of proteins. This happens in two stages:

  • Transcription is the first stage, where the DNA code is converted into an intermediate step called RNA.
  • Part of transcription is a process called splicing. Not all of the DNA code is needed to form the protein. The final RNA that will be used to make the protein is formed only from parts of the DNA code called exons. The other parts called introns are removed or spliced out.
  • Translation is the second stage where this RNA is converted into the protein.

The expansion in the C9ORF72 gene is found in an intron and seems to affect how the RNA is formed. In other words people with FTD or MND who have an expansion in the C9ORF72 gene have abnormal RNA as well as abnormal DNA.

Abnormal C9ORF72 forms G-quadruplexes

Previous studies have shown that the abnormal RNA leads to the formation of an unusual structure called a G-quadruplex that would not normally be found.

This latest study by Haeusler and colleagues at Johns Hopkins University in the US shows that both abnormal DNA and abnormal RNA form G-quadruplexes. In fact the DNA G-quadruplexes stop the C9ORF72 RNA from being formed properly. Multiple short pieces of RNA are formed instead and it seems to be these that are toxic to cells.

A new way to kill brain cells?

It is not yet clear why these abnormal short pieces of RNA are toxic to cells. The authors of this study suggest that one way they may be toxic is by the G-quadruplexes attaching themselves to a protein called nucleolin. Nucleolin is involved in the function of the nucleolus – a special compartment of the cell’s nucleus that is involved in the process called translation we talked about above. The C9ORF72 expansion might therefore be stopping the nucleolus from working in the correct way, a process called nucleolar stress.

The next step that follows from this study will be to confirm that nucleolar stress really is an important early event in the process that causes FTD and MND rather than just being secondary to brain cells dying off and no longer being able to be repaired.


Haeusler AR, Donnelly CJ, Periz G, Simko EA, Shaw PG, Kim MS, Maragakis NJ, Troncoso JC, Pandey A, Sattler R, Rothstein JD, Wang J. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature. 2014;507(7491):195-200.

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