Toxic proteins may cause motor neurones to die in C9orf72 MND

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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.

The background to C9orf72

Most cases of MND are thought to be caused by a combination of environmental, lifestyle and subtle genetic factors. However, we know that approximately 5-10% of all cases of MND are inherited. This means that they are characterised by a strong family history and the disease is caused directly by a mistake in a specific gene. Of these cases, the most common form is caused by a mistake in the C9orf72 gene where a segment of DNA is wrongly repeated thousands of times.

C9orf72 was first identified in 2011 as being the most common cause of inherited MND and the related neurodegenerative disease, frontotemporal dementia. Since then, researchers have been continually trying to understand more about this gene and how it causes both MND and frontotemporal dementia.

Three fruit fly families

There have been a number of ideas floating around the MND research community about how C9orf72 causes these diseases. The most common being toxic build up of RNA (our cell’s copy of DNA that is used to make proteins) and toxic repeat proteins.

Dr Adrian Isaacs and his team used fruit flies to find out whether or not it is the RNA or the proteins that are the main culprit in causing MND and frontotemporal dementia (find out more about why researchers use fruit flies here).

The researchers investigated this by creating three fruit fly families, which each had slightly altered C9orf72 mutations: One fruit fly family only made RNA; another only made protein; and a final fruit fly family made a combination of the two.

By comparing these slightly different fruit fly families the researchers were then able to find out whether the proteins or the RNA were involved in motor neurone death.

Fly eyes

Not only did the researchers compare the survival of the flies, they also studied eye degeneration in the fly. Eye degeneration in the fly has long been used by neurodegenerative disease researchers as a ‘window’ into the brain. This is because in fruit flies the eye is an extension of the nervous system, with eye damage also accompanied by nerve damage.

The researchers viewed this deterioration using highly powerful microscopes, enabling them to visualise what’s going on inside the fly. Dr Isaacs and his team found that the fruit flies, which made both the RNA and the protein, had decreased survival and increased eye deterioration. However the fruit flies that only made RNA were able to survive with no eye deterioration, highlighting that RNA alone is not toxic in C9orf72 MND.

Interestingly, the researchers found that the fruit flies that only made proteins, had decreased survival and increased eye deterioration to the same degree as the fruit flies that made a combination of protein and RNA.

This shows that the main culprit in motor neurone death in this C9orf72 form of MND and frontotemporal dementia is the toxic proteins produced from the RNA, and not the RNA itself.

What does this all mean?

Dr Adrian Isaacs
Dr Adrian Isaacs

Dr Isaacs and his team have identified that the toxic proteins produced by C9orf72 are the main cause of motor neurone death in inherited MND and frontotemporal dementia caused by the C9orf72 mutation. Toxic proteins may be the main cause of motor neurone death, however, the researchers have emphasised that this does not completely rule out RNA toxicity.

Dr Adrian Isaacs said: “I’m really excited about this research as we’ve found what we think causes the most common cause of inherited MND and frontotemporal dementia.

“We previously believed that the C9orf72 mutation produced a toxic type of RNA, but our research has shown that the RNA on its own is not toxic to motor neurones, but the proteins are.

“Finding out that the proteins produced by the C9orf72 mutation were toxic was a complete surprise, as we didn’t expect this at the start. Our next steps are to find out exactly how these toxic proteins cause the motor neurones to die and go on to try and develop drugs that stop their production. This research may be still a long way from therapy, first we need to confirm that what is happening in the fruit flies is also occurring in humans, but it’s a start in the right direction for combating one of the most common causes of inherited MND and frontotemporal dementia.”

Link to Alzheimer’s research UK press release

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