Closing the door on toxic proteins – new clues in understanding a genetic form of MND

The defects in the C9orf72 gene are known to cause motor neurone disease, but researchers don’t understand why. Defective copies of this gene are passed down in some families affected by the rare, inherited form of MND. This week MND Association grantees Drs Guillaume Hautbergue, Lydia Castelli and colleagues, based at the Sheffield Institute of Translational Neuroscience have published their research study providing some important clues about the toxicity of C9orf72. Their research is published in the prestigious journal Nature Communications.

What do we know about C9orf72 toxicity already?

When a link between a gene defect and MND is found, it opens up a new area of MND research. In order to be able to understand how to prevent the effects of the gene defect, we need to know what the gene does normally and how the defect changes this. We can then use this information to correct what has gone wrong and stop the motor neurones from dying. So far, we’ve got part of the picture of what is going wrong in the C9orf72-form of MND but we need more information.

There are three possible reasons why C9orf72 is toxic. One of these is the formation of short, abnormal and unwanted proteins called ‘dipeptide repeats’ or ‘DPRs’ in the cytoplasm of the cell. These are not seen in the absence of the C9orf72 defect.

What did the research study find?

Cells within our body contain a number of separated compartments, each carrying out specific functions. The blueprint for making up the thousands of proteins that carry out these functions is housed in the form of genes, in a compartment in the centre of the cell called the nucleus. A copy of the blueprint is created for each protein and is transported into the ‘open plan’ part of the cell, known as the cytoplasm. These copies serve as individual instruction manuals for the building of each protein and are called RNA.

We know that the defects in the C9orf72 gene blueprint are carried over into the RNA copy. The copy carrying the defects is then transported into the open plan part of the cell, where some of the toxic ‘DPRs’ are made. Dr Hautbergue and colleagues are looking in detail at the transport system between the nucleus and the cytoplasm, and a component called SRSF1 in particular.

They’ve done a series of experiments to look at SRSF1, starting in a fruit fly model of MND and ultimately doing experiments in motor neurones created using ‘iPSC’ technology from skin cells of people with MND (see blog of a few weeks ago for more on iPSCs).

When they remove SRSF1 from the cells or reduce the amounts of it, the researchers found that the C9orf72 toxic ‘DPRs’ form at much lower levels. In turn, this means that the motor neurones from MND flies or people with this form of MND live almost as long as motor neurones from healthy flies or healthy people respectively.

Importantly, they’ve also found that reducing the levels of SRSF1 has no effect on the function of the normal copy of C9orf72. In other words, SRSF1 is working with C9orf72 defective RNA to make the toxicity happen. SRSF1 is only needed to help the defective C9orf72 RNA go through the door from the central control system in the nucleus to the open plan part of the cell in the cytoplasm. Other RNAs go through this door normally all the time, without the help of SRSF1. So if we can develop a treatment that lowers the levels of SRSF1 it could close the door on the production of abnormal toxic components and motor neurones death.

“We have discovered a completely novel angle to tackle the abnormal protein components made in C9orf72-related MND and reduce their production in the disease” explained Dr Hautbergue. We first saw beneficial effects in a fruit fly model of MND. We can also increase the survival of human motor neurones, grown in the lab from the skin cells of C9ORF72-MND patients.

“This is the first time that such a strategy has been used to prevent the death of nerve cells. Our current research led to this prestigious publication and to a patent application. Both will help us collaborate with pharmaceutical industries for the development of pre-clinical and clinical studies – the starting point on a road to a potential treatment”.  

–Dr Guillaume Hautbergue

Original paper: Hautbergue et al. (2017) Nature Communications.

More information on this and other research projects that we fund can be found on the MND Association’s website.