Haplotype regulation of alternative splicing at the MAPT locus
Researchers Dr Richard Wade-Martins (principal investigator) and Ms Tara Caffrey
Institution Department of Physiology, Anatomy and Genetics, University of Oxford
Duration 2 years
Start February 2008 End January 2010
Grant £25,000
Aim of research
i) To understand the basis for genetic susceptibility to PSP
ii) To identify the DNA sequences responsible for the differences in MAPT gene expression and splicing between the H1 and H2 haplotypes.
About the research
The brain of a person with PSP contains protein aggregations, or neurofibrillary tangles, made of the microtubule associated protein tau (MAPT or tau). These tangles are made predominantly of a form of tau known as 4R tau, but it is not known why these tangles occur or why specifically the 4R form of the protein builds up.
Genetic studies have shown that people who carry a common form of the MAPT gene called H1 are more susceptible to PSP than people who carry the other main form of MAPT, H2. Recent work by Dr Wade-Martin's group at Oxford University has shown that the H1 form of MAPT makes more 4R MAPT than the H2 form of the gene. This is because H1 MAPT makes about 40% more MAPT carrying a fragment known as exon 10. The researchers suggest that the differing amounts of exon 10 produced by H1 and H2 may be the mechanism which makes carriers of H1 more likely to suffer from PSP. More recently, the researchers have shown that H1 and H2 make MAPT which varies at another place called exon 3. In this case H2 makes twice as much MAPT containing exon 3 than does H1. The researchers propose that the H1 variant makes carriers more susceptible to PSP by making MAPT with less exon 3 and more exon 10. On the other hand, H2 exerts its protective effect by making MAPT with more exon 3 and less exon 10.
In this project the researchers are focusing on identifying the DNA sequences responsible for regulating MAPT gene processing.
Findings
Work is in the early stages. Results from this research will be updated annually or sooner if there is exciting news.
What will the outcome of this research mean for people with PSP?
The results of this research will help us to develop a better understanding of the molecular and genetic mechanisms that lead to PSP. This knowledge will help to identify people at risk from the disease and hopefully will give some insight into how we may be able to develop a treatment for PSP.
Weblinks
Oxford Neuroscience - Richard Wade-Martins
University of Oxford - Wade-Martins Research