Two independent studies have suggested new targets for treating neurodegenerative diseases.
Errors in a process known as splicing, where the sections of a gene that don't code for the final protein product are cut out of a 'raw' copy of DNA (known as pre-mRNA), is known to produce dysfunctional proteins. These are associated with a number of neurodegenerative diseases, including Huntington's disease.
The first study, led by Dr Susan Ackerman of the Howard Hughes Medical Institute, USA, looked at RNA sequences which are essential to this splicing process - U-snRNAs. Using mice, the team focused on U2 snRNA, which is present in multiple copies in the nucleus and highly conserved in mammals.
'These copies are identical, or nearly identical, so conventional wisdom suggested they were redundant', says Dr Ackerman. 'For the first time, we show that a mutation in one copy can lead to disease'.
This mutation, in a single copy of a U2 snRNA called Rnu2-8, was sufficient to cause mis-splicing, leading to a build-up of abnormal proteins in the cell, loss of muscle co-ordination and neuronal degeneration.
Furthermore, the group noted that more mutant U2 snRNAs were found in the cerebellum, the part of the brain responsible for balance and co-ordination, indicating that their expression, previously thought to be universal, may vary depending on cell type.
Dr Ackerman says the next step is to see if the same effects are seen in humans, but that this 'opens up a whole new way of studying these RNAs'.
A second study looked at a repetitive sequence in the RNA, known as a triplet repeat. This is a series of three RNA 'letters' – in this case CAG – which, when repeated more times than normal is associated with a variety of neurological disorders. This extended triplet repeat enables the pre-mRNA to associate with a protein, a combination that causes defective splicing of the pre-mRNA.
A small molecule that binds to the RNA structure created by this repeat sequence RNA was found to improve splicing. As lead author Professor Matthew Disney of the Scripps Research Institute, USA, explains: 'For a long time previously it was thought that only the protein translated from this type of RNA was toxic. Our discovery... demonstrates that the RNA is toxic [as well]'.He continues: 'It also opens up new avenues for therapeutic development because we have clearly demonstrated that small molecules can reverse this type of defect'.