Long non-coding RNAs as regulators of human microtubule-associated protein tau (MAPT)

• Main Author: Javad, F.
• Other Authors: Hardy, J. ; de Silva, R. ; Ule, J.
• Published: University College London (University of London) 2016
• Subjects: 612.8
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.746345

Aggregation of the neuronal microtubule-binding protein, tau, is associated with cognitive decline and neuronal degeneration in tauopathies, including Alzheimer’s disease and frontotemporal dementia. In particular, changes in tau gene (MAPT) expression and splicing are directly linked with pathogenesis. Most genes, including MAPT, are now known to be associated with one or more sense/antisense non-coding RNA genes (ncRNA). We identified alternatively spliced variants of MAPT-AS1 that overlap in antisense with the MAPT 5’ promoter region, producing three transcripts, tau-NAT1, tau-NAT2s and tau-NAT2l (tNAT1, tNAT2s and tNAT2l, respectively) and investigated the role of these alternate isoforms in functional regulation of MAPT under physiological and stress conditions. The tau-NATs, with MAPT, are predominantly expressed in the brain and with increasing levels during neuronal differentiation of human fibroblast-derived iPSCs. Compared to tNAT1 and tNAT2l, the tNAT2s variant is most abundant and correlates with MAPT transcript levels in different brain regions. Using RNA-FISH we show that the tau-NATs are mostly present in the cytoplasm with some in nuclear spots that could be the sites of active transcription. To study the role of the tau-NATs in MAPT regulation, we created SH-SY5Y neuroblastoma clones stably expressing the tau-NAT variants and targeted deletions and mutants. Although full-length tNAT1 and tNAT2l do not effect MAPT gene transcription, they significantly repress tau expression at the translational level. By targeted deletions, we demonstrated that this translational repression requires the regions of 5’-5’ antisense overlap with MAPT as well as an MIR-repeat element in the 3’-domain of tNAT1 and tNAT2l. On the other hand, tNAT2s enhances tau translation due to additional regulatory elements. In this work, we further demonstrate that tNAT2s may have a selective role in heat-shock response whereby endogenous tNAT2s levels in SH-SY5Y cells are significantly elevated during heat shock with an accompanying increase in tau protein levels. Our data support a possible physiological role of MAPT-AS1 in post-transcriptional regulation of tau expression with a specific role of tNAT2s in cellular stress response.