Dysregulation of RNA Splicing in Tauopathies

Abstract

Summary: Pathological aggregation of RNA binding proteins (RBPs) is associated with dysregulation of RNA splicing in PS19 P301S tau transgenic mice and in Alzheimer’s disease brain tissues. The dysregulated splicing particularly affects genes involved in synaptic transmission. The effects of neuroprotective TIA1 reduction on PS19 mice are also examined. TIA1 reduction reduces disease-linked alternative splicing events for the major synaptic mRNA transcripts examined, suggesting that normalization of RBP functions is associated with the neuroprotection. Use of the NetDecoder informatics algorithm identifies key upstream biological targets, including MYC and EGFR, underlying the transcriptional and splicing changes in the protected compared to tauopathy mice. Pharmacological inhibition of MYC and EGFR activity in neuronal cultures tau recapitulates 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, as well as potential therapeutic targets for tauopathies. : RNA binding proteins are emerging as drivers of neurodegeneration. Apicco et al. show a dysregulation of RNA splicing in mouse and human tauopathies, with partial correction by reducing TIA1. A systems analysis suggests novel approaches for the therapy of tauopathy. Keywords: RNA splicing, tauopathy, TIA1, stress granule, NetDecoder, EGFR, MYC, transcriptome, RNA-seq, neuroprotection, RNA metabolism