Determine the Role of Human-Specific Tau Circular RNAs in Tauopathies

The microtuble binding protein tau expressed from the MAPT gene can misfold into paired helical filaments and neurofibrillary tangles that characterize tauopathies, which are neurodegenerative diseases that include frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Human MAPT contains 16 exons and generates six major protein isoforms due to alternative splicing. In contrast to mouse, MAPT exon 10 is alternatively spliced in the adult and encodes one of four microtubule binding sites, generating isoforms with different microtubule affinity. A change in exon 10 alternative splicing correlates with sporadic Alzheimer’s disease (AD) and mutations changing the usage of exon 10 cause FTDP-17. We have identified human-specific circular RNAs containing exon 10 generated by backsplicing of exon 12 to either exon 10 or 7a. These tau circRNAs are found in the cytosol and contain an open reading frame for exactly 288 and 681 amino acids with no stop codon. Thus, in a rolling circle mechanism these circular RNAs could potentially generate high molecular weight proteins made of multimers of MAPT parts. 48 of the 53 known FTDP-17 mutations are located in exons 9-13, i.e. in parts of the pre-mRNA that regulate the formation of the circ12->10 RNA, suggesting that FTDP-17 mutations could act through circular RNAs. There is now increasing evidence that circular RNAs can be translated after adenosine residues are methylated (N6mA) and bind to YTH proteins (N6mA-readers) that recruit ribosomal initiation factors. Importantly, heat shock and cellular stress promote circRNA translation. In humans, primate-specific Alu-elements promote circular RNA formation by forming secondary structures facilitating backsplicing which could explain the absence of the MAPT circRNAs we discovered in mice, rats and zebrafish. This human/primate-specific aspect of tau biology has never been investigated. Currently, there is no animal model available that tests the role of Alu elements in MAPT-pre-mRNA processing. We hypothesize that human-specific circular tau RNAs play a role in tauopathies, either by being translated into tau multimers or by sequestering factors necessary for linear tau processing. Cellular stress, possibly occurring after traumatic brain injury promotes translation or formation of these circular RNAs.