Dysregulation of RNA splicing in tauopathies

Pathological aggregation of RNA binding proteins (RBPs) has emerged as an important driver of multiple neurodegenerative diseases. Since RBP aggregation may result in a loss of normal RBP function, we examined whether dysregulation of RNA metabolism contributes to tauopathies. We find that the PS19 P301S tau mouse model exhibits a dysregulation of RNA splicing that is also apparent upon analysis of human Alzheimer’s disease brain tissues. Dysregulated splicing particularly affected genes involved in synaptic transmission. We also analyzed alternative splicing in PS19 mice crossed to a heterozygous TIA1 background, which has recently been shown to slow disease progression. TIA1 reduction alleviated several of the most significant alternative splicing events for synaptic mRNA transcripts, suggesting that normalization of RBP functions is associated with the neuroprotection. We then used a systems biology approach termed NetDecoder to identify key upstream biological targets, including MYC and EGFR, underlying the transcriptional and splicing changes in the protected compared to tauopathy mice. Importantly, pharmacological inhibition of MYC and EGFR activity in primary neurons overexpressing tau recapitulated the neuroprotective effects of TIA1 reduction. These results demonstrate that dysfunction of RBPs and RNA splicing processes are major elements of the pathophysiology of tauopathies, and identify new potential therapeutic targets for tauopathies.