FTLD-MAPT mutations and short 5'UTR Tau mRNAs increase Tau translation

Tau protein plays a central role in Alzheimer's disease (AD) and other tauopathies. Tau proteins aggregate in degenerating neurons and their expression level is critical for disease development and progression. In addition, the generation of truncated Tau species is involved in the pathological process. In the human brain, several N-terminally truncated Tau species (including Met11- and Met127-Tau) have been detected. However, both the mechanisms of their synthesis and their relevance for the diseases remain largely unclear. Several Tau messenger RNA (mRNA) isoforms with distinct 5' untranslated regions (5'UTRs) were found in brains with tauopathies. In addition, single substitutions in the N-terminal coding sequence of Tau, namely R5H, R5L and R5C, have been associated with AD, progressive supranuclear palsy and Parkinson's disease, respectively. Here, we investigated how the 5' end of Tau mRNAs and the N-terminal mutations affect Tau protein synthesis. We show that both the length of the 5'UTR of Tau mRNAs and the N-terminal coding sequence largely modulate the expression level of Tau. Truncated Tau protein species are generated by an alternative translation initiation event. Thereafter, we show that the disease-associated mutations at codon #5 also increase the expression, mostly due to secondary structure modifications of the corresponding mRNAs.