New exciting findings announced today provide the first insight into the structure and function of a repeated six letter genetic sequence in an MND gene called C9ORF72.
Understanding the function of C9ORF72, and how it could go wrong to cause MND, could assist researchers in the future to identify potential treatments that target the disease.
The finding was identified by University College London researchers including Dr Adrian Isaacs and Dr Pietro Fratta. Dr Fratta is a recipient of a Medical Research Council/MND Associaiton’s Lady Edith Wolfson Clinical Research Fellowship.
Their findings were published in the reputable scientific journal Scientific Reports on 21 December 2012.
C9ORF72 – the plot thickens
In 2011, MND Association funded researchers discovered that a repeated six-letter code within a gene called C9ORF72 can cause MND and a related condition called fronto-temporal dementia (FTD) for approximately 40% of cases with a family history of MND and/or FTD. Having a family history of MND is rare and affects 5-10% of people with MND.
In people without MND, this six-letter code (GGGGCC) is repeated up to 30 times. In C9ORF72 MND or FTD, this sequence can be excessively repeated between 700 and 1,400 times.
Since this pivotal discovery, researchers have started their journey to search for answers to find out more about C9ORF72 and how it can cause MND.
This study aimed to identify whether the six-letter code normally forms a specific structure when in its copy (RNA) form. Forming a structure normally means that something has a particular role. If this seemingly innocent piece of repetitive code does form a structure, then it could mean that excessively repeating it could cause problems by being over active, or by stopping other functions.
Dr Isaacs who led the study explains, “Nothing is currently known about how the mistake in C9ORF72 kills motor neurones. The mistake in C9ORF72 is similar to mistakes that cause some other neurological diseases.”
“In these diseases the mistake leads to the formation of toxic aggregates of RNA –RNA is a copy of DNA that is made when a gene is switched on and is important for the generation of proteins.”
Dr Issacs and colleagues used advanced analytical chemistry to identify the structure that the repeated six-letter code (GGGGCC) forms and to suggest its potential role.
RNA G-Quadruplex, glorified Battenberg cake
This shape, and structure that has been identified for the repeated six letter code in the copy of C9ORF72 is called an ‘RNA G-quadruplex’.
In real life terms, an RNA G-quadruplex would look –with some artistic license granted – like a Battenberg cake.
The four coloured sponge squares would be the individual letters of the code – all being the ‘GGGG’ part of the sequence running along the length of the structure and forming four ‘slices’.
Each line of four Gs (coloured length of sponge), is stuck together to another line of four Gs in the structure by strong hydrogen bonds (the jam!). This forms the four-square pattern that makes up each ‘slice’. Each line of four Gs is also attached to its phosphate backbone, which is the outermost section of the structure (the marzipan).
The only addition to the Battenberg that’s missing to create an RNA G-quadruplex would be a metal ball, or ion sitting in the middle of each of the four slices.
What does it do?
Having a structure means that the repeated six-letter code is of importance to find out whether it has a function. Having a function would then mean that the genetic expansion could have a detrimental effect on its usual role in the cell.
The forming of these Battenberg cake-like structures means that it could perform a specific role in the body. To date, quadruplexes have been identified as having a number of roles in the body, including editing copies of genes to create functional proteins.
Dr Pietro Fratta explains how this structure could play a role in C9ORF72 MND, “One possibility is that the RNA G-quadruplexes accumulate in motor neurones and then different proteins within the cell somehow bind to this structure and get stuck. As a result the motor neurones malfunction and perhaps even ultimately die.”
Commenting on these findings, MND Association’s Director of Research Development Dr Brian Dickie said “The UCL scientists have opened up an exciting new avenue of research.”
“At the moment we know very little about whether, or how, these RNA structures may be linked to MND, but evidence from other diseases indicates that they are biologically active and therefore likely to be important to the function and health of nerve cells.”
Following this finding, the next steps for researchers will be to determine the function of the G-quadruplex in nerve cells, and the effects of the excessive repeat in MND has on the function of these quadruplexes.
Paper reference: Fratta P. et al. C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Scientific Reports 2012 DOI: 10.1038/srep01016
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