Abstract
SUMMARYPathological 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.
Highlights
Microtubule associated protein tau (MAPT or tau) normally binds microtubules to stabilize the axonal cytoskeleton
We chose to analyze the transcriptome at the 9-month time point because this corresponds to an age where PS19 mice are severely affected by tauopathy, while P301S Tia1+/À mice are largely protected from the neurological and motor symptoms of disease (Apicco et al, 2018); non-transgenic tau mice exhibit no symptoms of disease or abnormal aging at 9 months regardless of Tia1 genotype
We first used next-generation RNA sequencing (RNA-seq) to analyze the differential expression of mRNA levels in PS19 compared to WT mice. 339 genes were discovered to be significantly up- or downregulated (FDR < 0.05) in the PS19 cortex (Table S1)
Summary
Microtubule associated protein tau (MAPT or tau) normally binds microtubules to stabilize the axonal cytoskeleton. Our group recently discovered that somatodendritic tau exerts an important biological function in regulating the translational stress response and the biology of RNA binding proteins (RBPs) This tau-mediated stress response is associated with a shift in protein synthesis and an increase in the formation of stress granules (SGs) that can lead to sequestration of RBPs in the cytoplasm (Vanderweyde et al, 2016). The role of somatodendritic tau in the biology of RBPs suggested that RBPs might reciprocally regulate the pathophysiology of tau Pursuing this hypothesis, we recently demonstrated that reduction of TIA1 in the PS19 P301S tau mouse model results in a delay of neurodegeneration, protection against behavioral deficits and a prolongation of lifespan (Apicco et al, 2018). The disease modifying effects of TIA1 reduction, the colocalization of TIA1 with somatodendritic tau, and the effects of somatodendritic tau on SG accumulation raise the possibility that dysfunction of RNA metabolism might be an important contributor to the pathophysiology of tauopathy
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