Control of tau gene expression
Lead researcher Dr Huw Morris
Co-researchers Professor Michael O'Donovan and Professor Michael Owen, Mr William Cross and Dr Elisa Majounie
Institution Department of Neurology, Cardiff University School of Medicine
Duration 38 months
Start February 2006 End April 2009
Grant £31701 (for pilot study) followed by £93119 research grant.
Aims of research
i) To conduct a pilot study to determine the feasibility of analysis of MAPT gene expression studies in post-mortem brain tissue
ii) To establish a DNA and RNA resource from patients with PSP
iii) To establish the effect of the MAPT H1 haplotype with respect to the expression of the MAPT gene and the potential effects of the risk haplotype.
About the research
This work followed on from my own and others earlier work looking at the genetic risk factors for PSP. Although MAPT (microtubule associated protein tau) is known to be a risk factor for the development of PSP, the mechanism by which it exerts its effect is unknown. The research involves the analysis of MAPT expression in brain samples (allele specific expression) and looking at variation in MAPT expression related to genotype.
The work has been undertaken in two phases - firstly, with a pilot study to establish the feasibility of the work followed by a two year research project.
The research work involves:
• Extraction of DNA and RNA from appropriate control and PSP autopsy brain samples
• Determination of allele specific expression indicating cis-acting control of MAPT expression in brain, using the major MAPT H1/H2 haplotypes
• Determination of allele specific expression for MAPT sub-haplotypes
• Determination of allele specific expression effects in PSP patients
• Determination of allele specific expression effects on the three repeat and four repeat variants of MAPT
• Sequence analysis of MAPT to determine relevant variants related to MAPT expression.
Findings
Work is in progress and we will update readers on developments annually or sooner if there are exciting new discoveries. But so far we have:
• identified an effect of age on MAPT expression, potentially providing some explanation for the effect of age as a risk factor for the development of PSP
• not identified a major effect of MAPT genotypes on the level of MAPT expression, although other groups have identified an effect particularly in four repeat tau.
We are currently working on ‘four repeat tau' and in applying this research to patients with PSP
What does the outcome of this research mean for people with PSP?
Future extension of this work is likely to relate to therapeutic agents that can affect the expression or alternative splicing of tau as these may be effective as disease modifying agents for PSP. Understanding how expression of the tau gene is controlled is an essential part of this process.
Publications arising from the work
Hayesmoore JB, Bray NJ, Cross WC, Owen MJ, O'Donovan MC, Morris HR. The effect of age and the H1c MAPT haplotype on MAPT expression in human brain. Neurobiol Aging. 2008 Feb 12; [Epub ahead of print].