Dementias, including Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD) and related diseases, become a leading challenge in our progressively aging society. The presence of tau protein-containing neurofibrillary tangles is a major neuropathological hallmark of AD and related dementia. Although RNA binding proteins (RBPs) are emerging as critical players in these neurodegenerative diseases, little is known about the RBP networks that control the balanced expression of the human tau gene or other dementia-associated genes (DAGs). Based on published studies and preliminary data, we propose to test the hypotheses that the RBP-tau regulatory networks that maintain balanced tau alternative splicing and tau mRNA expression are disrupted in tauopathies, leading to aberrant tau splicing and contributing to pathological tau aggregation and neurodegeneration. We plan to leverage the vast RNA-seq and proteomics data to construct RBP-tau gene regulatory networks and to use the newly developed human Tau knock- in (hTauKI) mouse model together with patient samples and iPSC neurons to validate key players contributing to the pathogenesis of dementia and related tauopathies. We will determine RBP genes and networks affected in dementia by examining candidate AD-associated RBPs in independent cohorts of patient samples using combined bioinformatics and molecular approaches (Aim 1). We will characterize RBP-tau RNA interactome using the hTauKI mice and using iPSC- derived neurons (Aim 2). We will determine the role of RBP-tau regulatory networks in tau neurotoxicity by dissecting molecular mechanisms of candidate RBPs in regulating tau pre-mRNA splicing and in tau pathogenesis (Aim 3). Our integrated multi-disciplinary approach combines bioinformatics with state-of-art molecular/biochemical assays with the brand-new hTauKI mouse model and iPSC-derived human neurons. This will enable us to construct RBP-tau regulatory networks critical for normal brain function and for tau pathogenesis. The proposed study will not only advance our understanding of complex post-transcriptional mechanisms regulating expression of DAGs and provide mechanistic insights into the function of RBP-tau networks, but also lead to information useful for developing new diagnostic and therapeutic tools for dementia.
|Effective start/end date||9/15/20 → 8/31/24|
- National Institute on Aging (1RF1AG068140-01)