Life of an MND researcher – part 2: PhD edition

Each year, the MND Association dedicates the month of June to raising MND awareness. This year, we focus on the eyes – in most people with MND the only part of their body they can still move and the only way left for them to communicate. Alongside the Association-wide campaign, the Research Development team selected six most-enquired about topics, which we will address through six dedicated blogs.

In our previous article we introduced four MND researchers who gave us an insight what a typical day in the life of a researcher looks like and what carrying out a research study actually involves. In this continuation article, you will get the chance to look into the lives of four PhD students, who give us an overview of their projects and their usual daily duties.Read More »

Funding for Gut-sy MND research announced

Yesterday the Reta Lila Weston Trust announced that they will be funding Dr Nikhil Sharma and colleagues at the Leonard Wolfson Experimental Neurology Centre (LWENC) to investigate whether the bacteria that live in our guts could alter the progression of MND. The grant is for £1.2 million over a period of four years. The LWENC is run jointly by the National Hospital for Neurology and Neurosurgery (NHNN) and University College London (UCL).

Incredibly, researchers have found a link between the bacteria that live in our guts and important cells called microglia. We know that microglia help regulate the function of the motor neurones. This study aims to find out whether the balance of gut bacteria in MND could be linked to changes in microglia.Read More »

Toxic proteins may cause motor neurones to die in C9orf72 MND

MND Association and Alzheimer’s Research UK-funded researchers from University College London have identified that toxic proteins may cause motor neurones to die in C9orf72 MND and frontotemporal dementia. Published open access in the journal Science on Thursday 7 August, this research explains more about one of the most common forms of inherited MND.

The brain of a transgenic fruit fly Drosophila melanogaster, used to study neurodegenerative diseases, with cell nuclei (stained purple) and glial cells (green). Image courtesy of Teresa Niccoli, UCL Institute of Ageing, London, UK.

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Structure of C9ORF72 repeat identified by MND Association funded researchers

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 Adrian Isaacs
Dr Adrian Isaacs

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.

RNA G-quadruplex looks 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
Dr Pietro Fratta

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

Read our news release on this story.