New fellowship explores how C9ORF72 causes MND

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Dr Johnathan Cooper-Knock
Dr Johnathan Cooper-Knock, MRC/MND Association Lady Edith Wolfson Clinical Research Fellow

Dr Johnathan Cooper-Knock from the Sheffield Institute for Translational Neuroscience (SITraN) has been awarded with the fifth Medical Research Council (MRC)/MND Association Lady Edith Wolfson Clinical Research Fellowship.

Through his three-year fellowship, Dr Cooper-Knock will use the MND Association’s DNA bank to study how recently discovered mistakes (known as mutations) in a gene called C9ORF72 can cause the disease.

Dr Johnathan Cooper Knock explains, “I believe that the genetics of MND are a key to understanding both the cause of the disease and how to treat it. The discovery of mutations in C9ORF72 are a great opportunity to get a hold on mechanisms of disease which has so far been elusive. I am excited by the opportunity my fellowship will give me to pursue this important discovery.

“By the end of my fellowship I aim to have contributed significantly to the understanding of disease mechanisms related to C9ORF72 dysfunction in MND. As a result I hope to have identified a number of therapeutic targets for development into new treatments by myself and others.”

C9ORF72: the facts so far

We know 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 positive family history of MND and/or FTD.

Most genetic mistakes found in MND to date have been swaps of genetic letters, which can change the meaning of that part of the gene. The C9ORF72 genetic mistake on the other hand, is a repeat expansion. This means that six letters within the genetic code (CCCCGG) are repeated hundreds of times for people with C9ORF72 MND. In healthy individuals, this repeat is found about 30 times. We already know that the exact size of the repeat varies substantially between people with this genetic mistake. How this repeat causes MND and how the size of the repeat may affect disease progression is currently unknown but this is something that Dr Cooper-Knock wants to find out.

We also don’t know what role C9ORF72 normally has in the body. Even its name, which stands for ‘chromosome 9 open reading frame 72’ refers to where it is in the genetic code and not what it does. This isn’t unusual as it’s currently estimated that we have over 20,000 genes, and understandably, researchers haven’t yet found out what every one of these does – including C9ORF72.

So far, 96 journal articles have been published about C9ORF72 (by searching on Pubmed for C9ORF72). The oldest of these was published in 2011, and describes the original MND/FTD C9ORF72 finding. All subsequent articles on C9ORF72 have been of a direct consequence from this pivotal genetic discovery in the past year.

These 96 studies were focused on finding out how many people have the C9ORF72 genetic repeat and finding out what this mistake ‘looks like’ both clinically in terms of progression rates, age of onset and symptoms; and in terms of post-mortem findings to compare with other forms of MND. Coincidently, the most recent post-mortem and clinical C9ORF72 finding was authored by Dr Cooper-Knock (when searching for C9ORF72 and post mortem on PubMed).

It’s reassuring to know that researchers aren’t resting on their laurels with this genetic finding. There’s a huge international research effort in place to push forward our understanding of C9ORF72, with a number of our own newly funded projects, starting later this year, dedicated to creating new laboratory models of this genetic mistake to better understand how it can cause the disease.

How do we currently think C9ORF72 causes MND?

Due to the sheer size of the repeat expansion in C9ORF72, it’s thought that it causes MND by disruption of the editing process of genetic information.

I’ll explain: In real life terms, our DNA can be thought of as being held within a library, which is the control centre of the cell (the nucleus). Each book (gene) is stored on a particular shelf (chromosome). Gene ‘books’ aren’t allowed to be taken out of the nucleus, but they can be photocopied. These copies (RNA) are edited and transported out of the nucleus to be used as instructions to create proteins that perform specific roles in and sometimes out of the cell.

Unlike real life books, genes are fraught with errors, variations and nonsense from one person to the next. It looks messy, but it’s normal. Genetic editors are needed to edit and chop the RNA into a readable format so that it can be understood by the parts of the cell that use RNA as instructions.

As normal, healthy copies of C9ORF72 hold approximately 30 repeats to be chopped out as RNA, the effect of having much larger repeats may be having a knock-on effect on the efficiency of the editing process. This could then lead to a much higher risk of developing MND.

Finding out exactly how C9ORF72 can cause MND, and whether this theory is right, will provide us with a deeper insight into MND and potentially provide therapeutic targets that can be further investigated.

Dr Cooper-Knock’s fellowship

Dr Cooper-Knock will be using a cutting-edge genetic technique called ‘gene expression profiling’ to study the various levels of RNA in samples provided by people with the C9ORF72 genetic mistake. From this, he’ll find out which genes are switched on and off because of the C9ORF72 repeat expansion.

He will also study whether the size of the C9ORF72 repeat expansion has an effect on symptoms or progression rates to identify factors that may modify disease progression and may therefore be targets for future therapies.

Technology specialised for identifying misassembled RNA will also be applied to skin cells donated by people with the C9ORF72 repeat expansion who have MND/FTD and healthy controls. This will help to elucidate what the C9ORF72 protein does.

As well as skin cells from people with MND/FTD, this study will use post-mortem brain and spinal cord tissue from people with the C9ORF72 repeat expansion and healthy controls within the Sheffield tissue bank; as well as cells from the blood of C9ORF72 patients and healthy controls obtained from the MND Association’s DNA Bank.

Talking about the importance of people with MND having provided these numerous samples Dr Cooper-Knock said “Without the participation of patients and their families MND research will get nowhere; and equally with their participation, doors are opened towards new and exciting treatments. At this time, with discoveries like the mutations in C9ORF72 to build from, we can do even more with the participation of those who have been affected by this disease, who like us are passionate to see it cured.”

More information:
Read our official news release on our MND Association website.
Find out more about our DNA bank.

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