Wednesday, 1 July 2015

Little bits of history repeating….

One of the biggest discoveries in MND research in recent years has been the discovery that mutations of a gene with the rather snappy name of C9ORF72 are one of the most common causes of MND. This mutation takes the form of several thousand repeats of the sequence GGGGCC in the middle of the gene, so the sequence goes GGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCC and so on for a few thousand repeats.

A gene is a code written in DNA that is the recipe for making a protein. Proteins are the building blocks and building tools for making cells, tissues, organs and bodies. To make a protein, the cell first copies the DNA gene code to RNA, then processes and prepares the RNA copy, then uses that as the template pattern for the protein.

MND researchers are spending a lot of time trying to work out how this repeat causes disease: The options are 

1) the cell can’t make enough of the protein encoded by C9ORF72 because of the cumbersome GGGGCCGGGGCC (etc) repeat stuck in the middle of it. 

2) The molecular tools that process RNA copies of genes get stuck to the repeat, so there aren’t enough of these tools left over to process RNA copies of other genes.  

3)  The cell gets confused and tries to use the GGGGCCGGGGCC repeat as a template to make rather odd proteins that shouldn’t exist and deposits them as ‘repeat inclusions’ in the cell and these are in some way toxic to the cell.

Repeating sequences in genes have been known to cause many other diseases, and the same scientific question applies: Is it poor protein production, disrupted RNA processing or trying to turn the repeat into protein that causes the problem. A very commonly repeated sequence is CAG which can cause Huntington’s disease, Kennedy’s disease (another motor neurone disease) and a number of diseases called “spinocerebellar ataxias” which result in problems of the spinal cord and cerebellum, the part of the brain at the back that aids coordination and balance. Long repeats of CAG in the gene ATXN2 cause spinocerebellar ataxia type 2.

Here’s the surprising issue: While long CAG repeats in ATXN2 cause spinocerebellar ataxia, medium-sized repeats of CAG in ATXN2 cause motor neurone disease. We looked at the brains and spinal cords from MND patients who had medium-sized repeats. Like patients with C9ORF72 they get the normal microscopic features of MND, but they don’t seem to have the repeat inclusions. Which makes us think more carefully about the other 2 options: not enough protein and disrupted RNA processing, both in ATXN2-MND and C9ORF72-MND and possibly non-inherited cases as well.

Much of the work was done by Alejandro Lorente Pons whilst studying for his MSc in Translational Neuroscience. He enjoyed this so much he stayed on with us to do a PhD in MND research – good choice Ale! 

The research presented here is now published in the journal
Neuropathology and Applied Neurobiology:

J R Highley, A Lorente Pons, J Cooper-Knock, S B Wharton, P G Ince, P J Shaw, J Wood and J Kirby. Motor neurone disease/amyotrophic lateral sclerosis associated with intermediate length CAG repeat expansions in Ataxin-2 does not have 1C2-positive polyglutamine inclusions. Epub June 2015

By Dr Robin Highley, Senior Lecturer in Neuropathology

Find out more about my research on the SITraN website.

You can follow me on
Twitter @JRobinHighley
and on ResearchGate.


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