The recent identification by our group of mutations in the 5' splice site of tau exon 10 that are associated with Fronto-temporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) demonstrated for the first time that the ratio of Tau containing 4 and 3 microtubule binding repeat is crucial to the correct functioning of Tau in the adult Human brain. The splice site mutations (+3, +13, +14 and +16) all destabilize a stem-loop structure that is likely involved in regulation of exon 1- alternative splicing by inhibiting U1 snRNP binding and exon definition. The mutations are thought to cause increased U1 snRNP binding, through disruption of the stem-loop, which directly leads to increased splicing of exon 10 and increased 4 repeat Tau. We were the first to demonstrate that the mutations increasing splicing of exon 10 and increased 4 repeat Tau. We were the first demonstrate that the mutations increased splicing of tau exon 10 by RT-PCR analysis of FTDP-17 brains and also through the use of an in vitro splicing assay. Further we have since demonstrated, using the in vitro splicing assay, that it is indeed the stem-loop structure in the 5' splice site of exon 10 that is disrupted by the FTDP-17 mutations that which plays a major role in the regulation of alternative splicing of this exon. The fact that mutations that increase the proportion of 4 repeat Tau by as little as two fold are pathogenic in FTDP-17 indicates the importance of the ratio of Tau isoforms with 3 and 4 repeats to the correct functioning of Tau. In other species the ratio of 4 repeat to 3 repeat Tau can vary widely and in addition it has been known for some time that in fetal brain only 3 repeat Tau is observed with the generation of 4 repeat isoforms not occurring until some time after birth. Thus the 4 repeat to 3 repeat Tau ratio seems virtually certain to reflect if not to underlie, some fundamental differences in the role of neurons in different species and during development. This project is designed to increase our understanding of the regulation of the ratio of 4 to 3 repeat Tau, why this ratio is important in the correct functioning of neurons and why disruption of this ratio can result in neurodegeneration.
Showing the most recent 10 out of 215 publications
