Tau mis-splicing corrected
30 September 2009
Recent genetic research has shown that a molecular process called pre-mRNA alternative splicing is central to the development of neurodegenerative diseases. The complexity of alternative splicing and its regulation makes it a difficult target for conventional therapies. In a paper published recently in the journal Human Molecular Genetics, a team from the MRC Centre for Neurodegeneration Research, Institute of Psychiatry at King’s, led by Dr Jean-Marc Gallo, has used a state-of-the-art RNA reprogramming method to correct aberrant splicing causing a rare form of dementia – frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) - by affecting variants of the tau protein.
The method the team used is called spliceosome-mediated RNA trans-splicing (SMaRTÒ, a proprietary technology of the US company, VIRxSYS) with which a part of an mRNA can be added, removed or replaced. The team had shown previously that alternative splicing could be experimentally manipulated using SMaRT. In the new study, they show that the production of tau variants missing as the result of pathogenic FTDP-17 mutations could be restored.
Dr Gallo said: 'This is the first evidence that the effects of pathogenic mutations on splicing can be corrected experimentally. The next challenge will be to translate these findings into the clinic. Gene therapy for brain diseases is still at an early stage, but the availability of very effective viral vectors makes therapeutic application of SMaRT for neurological disorders a realistic possibility.'
This research opens the way to novel therapeutic strategies for a wide range of neurodegenerative diseases. It shows that RNA-based methods at the forefront of today’s therapeutic methods are at hand to tackle emerging mechanisms being discovered in neurodegeneration.
The study was supported by the Wellcome Trust, the Biotechnology and Biological Sciences Research Council, the Medical Research Council, Ataxia UK, the Alzheimer’s Research Trust and the Psychiatry Research Trust.
The authors of the paper are Rodriguez-Martin T., Anthony K., Garcia-Blanco M.A., Mansfield S.G., Anderton B.H. and Gallo J.-M. (2009). Correction of tau mis-splicing caused by FTDP-17 MAPT mutations by spliceosome-mediated RNA trans-splicing.Hum. Mol. Genet. 18: 3266-3273. A copy of the paper can be viewed here: http://hmg.oxfordjournals.org/cgi/content/full/18/17/3266