Testing the neuroinflammatory role of tau-induced transposable elements in tauopathy

BACKGROUND: Novel mechanisms through which pathogenic tau leads to neuronal toxicity remain largely unexplored as therapeutic targets for tauopathies. Activation of retrotransposons has been identified as a mechanism by which pathogenic tau contributes to neurotoxicity (Guo et al., 2018; Sun et al., 2018). To mobilize, retrotransposons are transcribed into RNA, reverse transcribed into DNA, and reinserted into the genome in a new location. Control of retrotransposons occurs at two levels, 1) transcriptional control via the location of retrotransposons within highly condensed heterochromatin and 2) by post-transcriptional silencing mechanisms. While activated retrotransposons can create novel mutations via the "copy-and-paste" mechanism, double stranded RNAs (dsRNAs) formed from transposable element transcripts trigger the innate immune response, further contributing to cell toxicity (Cuellar et al., 2017; Kassiotis & Stoye, 2016; Roulois et al., 2015). Elevation of dsRNAs is documented in models of AGS and TDP-43 proteinopathy, where dsRNA derived from repetitive elements can stimulate an interferon response (Ahmad et al., 2018; LaRocca, et al., 2019; Rodriguez et al., 2021).We are currently testing the hypothesis that transposable element-derived dsRNAs stimulate the immune response in tauopathy. METHOD: Bioinformatic analysis of bidirectional transcription was completed on RNA-sequencing data from control and tau transgenic Drosophila. dsRNAs were quantified by J2 anti-dsRNA antibody via immunofluorescence and ELISA. Analysis of inflammatory markers in Drosophila was completed by RNA-sequencing and with a custom NanoString Gene Expression codeset. RESULT: We find that dsRNAs are elevated in the brains of tau transgenic Drosophila, in the cortex of a mouse model of tauopathy, and in post-mortem brain tissue from human tauopathy. Based on bioinformatic analysis, we identified retrotransposons that are bidirectionally transcribed in tau transgenic Drosophila. RNA sequencing and NanoString analysis of tau transgenic flies reveals elevated levels of innate immune response gene transcripts. Loss of transposon transcriptional silencing results in similar dsRNA production and immune system activation found in tau transgenic Drosophila. CONCLUSION: Our goal is to determine if RNA intermediates from tau-induced transposable elements are a therapeutic target for tauopathies. Overall, our findings support a model where dsRNA production induced by loss of transcriptional transposon silencing contributes to inflammation in tauopathy.