A new non-aggregative splicing isoform of human Tau is decreased in Alzheimer\u2019s disease

Vega García-Escudero,Esther García,Raquel Cuadros,Jorge R Cabrera,Mar Pérez,Ramón García-Escudero,Ricardo Gargini,Daniel Ruiz-Gabarre,Ivó H Hernández,Félix Hernández,José J Lucas,Jesús Ávila

doi:10.1007/s00401-021-02317-z

Abstract

Tauopathies, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration with Tau pathology (FTLD-tau), are a group of neurodegenerative disorders characterized by Tau hyperphosphorylation. Post-translational modifications of Tau such as phosphorylation and truncation have been demonstrated to be an essential step in the molecular pathogenesis of these tauopathies. In this work, we demonstrate the existence of a new, human-specific truncated form of Tau generated by intron 12 retention in human neuroblastoma cells and, to a higher extent, in human RNA brain samples, using qPCR and further confirming the results on a larger database of human RNA-seq samples. Diminished protein levels of this new Tau isoform are found by Westernblotting in Alzheimer’s patients’ brains (Braak I n = 3; Braak II n = 6, Braak III n = 3, Braak IV n = 1, and Braak V n = 10, Braak VI n = 8) with respect to non-demented control subjects (n = 9), suggesting that the lack of this truncated isoform may play an important role in the pathology. This new Tau isoform exhibits similar post-transcriptional modifications by phosphorylation and affinity for microtubule binding, but more interestingly, is less prone to aggregate than other Tau isoforms. Finally, we present evidence suggesting this new Tau isoform could be linked to the inhibition of GSK3β, which would mediate intron 12 retention by modulating the serine/arginine rich splicing factor 2 (SRSF2). Our results show the existence of an important new isoform of Tau and suggest that further research on this less aggregation-prone Tau may help to develop future therapies for Alzheimer’s disease and other tauopathies.

Highlights

Materials and methodsTau is a microtubule-associated protein (MAP) that acts as a neurite microtubule stabilizer [9, 61]
New alternative splicing variant of MAPT present in mature human transcriptome Recently, the presence of new protein isoforms generated by intron retention in neurodegenerative diseases such as Alzheimer’s disease [45] and Huntington’s disease [52] has been described
Human intron 12 includes a canonical stop codon sequence followed by a polyadenylation canonical site, so intron 12-containing species would be translated as a truncated protein similar to the truncated isoform mediated by asparagine endopeptidase (AEP) (ET-Tau), with 18 more amino acids, which we have named W-Tau (Fig. 1a)

Summary

Introduction

Materials and methodsTau is a microtubule-associated protein (MAP) that acts as a neurite microtubule stabilizer [9, 61]. RNA-seq data from 363 samples from 3 different brain regions of 180 healthy donors were used to confirm the existence of TIR-MAPT transcripts (Supplementary Table 3, online resource).

Results

Conclusion