Over the summer I travelled over the Healy mountain Pass in Ireland – my memory of the drive is lots of hairpin bends. Fast forward six months and I’m reminded of those bends at the first day of the International Symposium – this time we’re talking about hairpins in RNA rather than roads!
RNA is the template between the instructions in our DNA and the final production of a protein – a protein that has been made, folded and ready for action. This simple description of RNA being a template hides so many different jobs that RNA performs behind the scenes (perhaps a bit like organising the International Symposium itself!). We know that this hotbed of reading and processing to make functioning proteins is a weak spot in motor neurones – and is one of the things that goes wrong in MND. We don’t know what goes wrong in RNA’s many jobs or how it goes wrong – so Session 2A of the symposium this morning was exploring this in more detail.
Back to hairpins
The way RNA reads DNA instructions is like two halves of a zip coming together. In some diseases, such as the C9orf72 repeat defect in MND, the RNA half of the zip folds back in on itself to create a hairpin. The problem with this RNA hairpin is that it makes unplanned and unwanted fragments of protein called dipeptide repeats or ‘DPR’s. The process that makes the unwanted protein fragments is called RAN – repeat associated ATG translation. Prof Laura Ranum first spotted these RANs and she opened this session of the symposium with a background on their importance in neurodegenerative diseases, and the ‘C9orf72 repeat’ defect found in MND and frontotemporal dementia in particular.
Reading in the right direction
When it is assembled, the instructions within DNA only make sense reading them in one direction. This is just the same way that words are written to be read in one direction. There are occasional words such as ‘pan’ and ‘nap’; or ‘top’ and ‘pot’ that can be read in both directions, but their meanings are completely different. Continuing the theme of talking about the C9orf72 repeats present in MND, Dr Johnathan Cooper-Knock, MND Association funded Lady Edith Wolfson Clinical Research Fellow looked at which way the DNA is read to create RNA – either the correct ‘sense’ way, or the opposite direction – so called ‘antisense’. He found that the presence of antisense RNA was linked with the toxic change of locations in motor neurones of a protein called TDP43. Reading the DNA in the sense direction didn’t have the same effect. In other words, Dr Cooper-Knock showed that the antisense RNA is toxic and the sense RNA isn’t.
“Our data suggests that neurons which die process the mutated gene in a different way to less vulnerable neurons, and we hope to exploit this to design new treatments. This work would not have been possible without the funding of the MND Association through the Lady Edith Wolfson fellowship scheme”, commented Dr Cooper-Knock.
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