Researchers from the Sheffield Institute for Translational Neuroscience (SITraN) at the University of Sheffield have uncovered a new function of the C9orf72 protein. A paper on their work has recently been published in the EMBO Journal.
A change or mutation to the C9orf72 gene is linked to about 40% of cases of inherited MND. We also know that changes to this gene also occur in a type of dementia called frontotemporal dementia (FTD). However, the reasons behind this link have so far been unclear.
One of the main research routes towards explaining the link between the C9orf72 gene and MND is to work out the normal function of this gene. By studying the protein the gene produces, researchers can see how alterations to this protein and the processes it is involved with result in nerve cell damage in MND.Read More »
PhD student Emma Smith has recently started the second year of her MND Association-funded research project at the Sheffield Institute for Translational Neuroscience (SiTRAN) in Sheffield (our project reference: 870-792). With her supervisors Dr Kurt De Vos and Dr Andrew Grierson she is investigating the role of mitochondria in C9orf72-related MND.
Mitochondria are the cell’s batteries, providing them with energy. Earlier research has linked damage to mitochondria as a contributor to why motor neurones die in MND. Based on preliminary evidence, the team are aiming to find how the C9orf72 protein causes damage to the mitochondria, where it happens and what might be done to prevent it.Read More »
In 2011 an international team of scientists, including three MND Association-funded researchers, identified the elusive C9orf72 gene located on Chromosome 9. Since this ground-breaking discovery, researchers from around the world have been trying to find a way to open-up and reveal more about this MND-causing gene.
Determined to get inside and unravel the secrets behind C9orf72, the Association is funding a number of new and exciting research projects to help solve the mystery. These projects look at, not one, but a number of different aspects to try and understand more about C9orf72.
In order to solve this mystery our C9orf72 researchers are following the clues using zebrafish, mice, flies and DNA samples.
How the C9orf72 MND mystery began
We each contain copies of 23 pairs of chromosomes, including the X and Y sex chromosomes. These chromosomes contain thousands of genes that portray our characteristics such as hair and eye colour. These genes are made up of DNA which can either be ‘coding’ to make a protein, or ‘non-coding’. For details of how genes make a protein see our earlier blog post.
Before C9orf72 was identified researchers had focused on an area on Chromosome 9 that appeared to be connected with both the rare inherited form of MND and the related neurodegenerative disease frontotemporal dementia (FTD).
Using a number of cutting-edge techniques the international team isolated the C9orf72 gene expanded GGGGCC hexanucleotide repeat as being a crucial player in both inherited MND and FTD. Not only did the researchers find a link between MND and FTD, they also found that C9orf72 was found in approximately 40% of cases of inherited MND (where there is a strong family history). This means that we now know 70% of the genes that cause the rare inherited form of MND. For more details on C9orf72 see our earlier blog post.
So, researchers found C9orf72. The next question was ‘What does it do? Is the gene defect repeat itself, or the protein it makes responsible for causing MND? And what goes wrong in MND?’
Two recent research clues
Since 2011 researchers have been trying to answer these questions and find out more about C9orf72. This has led to a dramatic increase in research, including two papers published in February and March this year!
Prof Christian Haass (Munich Centre for Neurosciences, Germany), who recently presented at our 23rd International Symposium on ALS/MND in December 2012, published a paper on the 7 February in the journal Science. The second paper lead by Prof Leonard Petrucelli (Mayo Clinic, USA) was published open access in the journal Neuron on the 20 February.
In a big surprise, both researchers found that the presumed ‘non-coding’ C9orf72 GGGGCC repeat expansion actually made a protein. Normally these ‘non-coding’ regions do not make proteins so this was a very big surprise indeed!
The researchers found that these proteins formed large clumps in the brains, and throughout the central nervous system (CNS), of people with C9orf72 MND and/or FTD. Importantly, they did not find these clumps in healthy individuals or those with other neurological disorders.
It is currently unknown as to whether these protein clumps are involved in MND and/or FTD, but they may be a potential biomarker or a therapeutic target in this most common type of MND. The next step is for the researchers to find out whether these proteins actually cause MND and/or FTD.
Finding more evidence to piece together the clues
In addition to these two papers looking into the mystery behind C9orf72, the Association is funding some exciting new research projects, each looking at different things, to further understand more about this gene.
Dr Johnathan Cooper-Knock (Sheffield Institute for Translational Neuroscience, UK) is already trying to identify how C9orf72 causes MND by utilising a genetic technique known as gene expression profiling. He is using samples from the Association’s DNA bank which are positive for the C9orf72 genetic mistake. Gene expression profiling is a technique which allows researchers to understand how the activity of genes contributes towards causing MND. (Traditional genetic studies are designed to look at which genes are affected, rather than their activity – ie when and how). Read more about Johnathan’s project here.
Developing new disease models enables us to understand the causes of MND and to test new therapies. One way to understand the function of C9orf72 and how this goes wrong in MND is to create a model. Our current research projects are developing new C9orf72 models in flies, mice and zebrafish.
Dr Frank Hirth (Kings College London, UK) will be producing a fly model, Dr Javier Alegre Abarrategui (University of Oxford) will be making a mouse model and Dr Andrew Grierson (University of Sheffield, UK) will be creating a zebrafish model.
All of our C9orf72 Association-funded research projects are using different approaches to look at C9orf72 in different ways as we are still unsure whether the protein or the repeat is the problem. From mice to flies all of these research projects together are helping to solve the mystery of C9orf72 and MND.
With the proteins formed by C9orf72 likely to be a potential biomarker or therapeutic target the two recent papers are adding to the growing number of clues, pointing researchers in the right direction to unravelling and solving the secrets of C9orf72.
Mori, K. et al. The C9orf72 GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD/ALS. Science. 339(6125): 1335-1338.2013 DOI: 10.1126/science.1232927
Ash, P. E. A. et al. Unconventional Translation of C9ORF72 GGGGCC Expansion Generates Insoluble Polypeptides Specific to c9FTD/ALS. Neuron. 77(4): 639-646. 2013 DOI: 10.1016/j.neuron.2013.02.004