Toxic proteins implicated in frontotemporal dementia and motor neurone disease

Scientists at UCL Institute of Neurology and the Max Planck Institute for Biology of Ageing in Cologne have discovered how a specific genetic mutation may damage nerve cells in frontotemporal dementia and motor neurone disease.

The research, which suggests a potential new target for treating the two brain diseases, was funded by Alzheimer’s Research UK, the Motor Neurone Disease Association, the UK Medical Research Council (MRC) and the Wellcome Trust. The study was published in the journal Science.

The researchers used fruit flies to better understand the effects of the C9orf72 gene, which has been linked to both frontotemporal dementia (FTD) and motor neurone disease.

A faulty version of the C9orf72 gene was recently shown to cause both FTD and motor neurone disease, and is thought to be responsible for roughly 8% of all cases of each disease in the UK.

The faulty gene contains a short section of genetic code that is repeated thousands of times. This repeated code results in extra molecules called RNA, as well as repeated fragments of protein, and the challenge has been to uncover whether the RNA or the protein – or both – may be harmful to nerve cells.

The research team first worked to ‘clone’ sections of DNA in a way that produced only RNA, only protein fragments, or RNA and protein together. They then used fruit flies to study the effects of both the RNA and protein. They found that although RNA on its own did not result in any damage to nerve cells, artificial DNA that produced RNA and protein, or only protein, caused striking damage to nerve cells and shortened the lifespan of the flies.

The results suggest that toxic protein fragments are the main culprit in causing brain cell death in both diseases.

Further experiments showed that the toxic effects could be traced to two particular types of protein fragment – those containing high amounts of an amino acid called arginine.

Dr Adrian Isaacs of UCL’s Institute of Neurology, senior author of the research, said:

“Our findings were also surprising because our earlier results showed that people with FTD have a build-up of RNA in certain brain regions, and one future avenue for research will be to determine what role this RNA build-up may play in the disease.”

Further information

• S Mizielinska et al. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science. Available online 7 August 2014. DOI: 10.1126/science.1256800
• UCL press release
• Alzheimer's Research UK press release

• Lashley T, et al. A pathogenic progranulin mutation and C9orf72 repeat expansion in a family with frontotemporal dementia. Neuropathol Appl Neurobiol. 2014 Jun;40(4):502-13. doi: 10.1111/nan.12100.
• Mizielinska S, et al. C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci. Acta Neuropathol. 2013 Dec;126(6):845-57. doi: 10.1007/s00401-013-1200-z.
• Dr Adrian Isaacs' academic profile on IRIS

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