Tau missplicing caused by RNA processing proteins located on chromosome 21 Trisomy 21 (Down syndrome, DS), the most common chromosomal disorder (incidence of about 1:800), results in morphological defects, mental retardation and early-onset dementia with Alzheimer characteristics, including neurofibrillary tangles. Neurofibrillary tangles are causative and diagnostic structures found in the brains of all dementia sufferers, including DS, Alzheimer's disease, frontotemporal dementia with Parkinsonism (FTDP) and myotonic dystrophy 1. The major component of tangles is abnormally phosphorylated tau protein. The neuronal microtubule-associated protein tau undergoes complex alternative splicing and differential phosphorylation, producing isoforms with different ligand affinities and functions. Our work and that of others has shown that misregulation of tau exon 10 splicing causes FTDP and that exon 10 ratios are also altered in AD. In this exploratory grant, we propose to test the hypothesis that an overdose of RNA processing proteins located on chromosome 21 causes errors in the splicing regulation of tau and its splicing regulator clk2, which in turn contributes to the early dementia aspects of DS.
The aims of the grant are to investigate: 1) Regulation of tau and clk2 splicing by RNA processing proteins located on chromosome 21. These include SR-A4, RBM11, U2AF35 and PCBP3 (hnRNPE3). Our work has shown that hnRNPE2, a close relative of hnRNPE3, regulates tau splicing. 2) Possible missplicing of tau and clk2 by incorrect expression of phosphorylation factors located on chromosome 21. These include MAKV (HUNK), KID2 (SFN1LK) and MNB (Dyrk1A). Dyrk1A localizes to nuclear speckles and our work has shown that it also phosphorylates factors which regulate splicing of tau exon 10. 3) The expression and localization profile of factors located on chromosome 21 that we find to influence tau and clk2 in brains of human individuals who are normal or diagnosed with DS and AD. Results from testing this novel hypothesis should 1) establish novel predictive biomarkers for trisomy 21 dementia, 2) uncover additional connections between trisomy 21 mental retardation and early-onset dementia and 3) offer the possibility of treatment options via manipulation of kinases with a restricted expression profile and substrate specificity. The prevalence of the syndrome and its clear connection to AD make this hypothesis a very relevant and potentially fruitful subject of study. Tau missplicing caused by RNA processing proteins located on chromosome 21 These studies will clarify the elusive connections between tau and the early-onset dementia aspect of Down syndrome. They may also help us find therapeutic targets and treatment options for this extremely prevalent and agonizing genetic disease. ? ?
