Sirt1 enhances tau exon 10 inclusion and improves spatial memory of Htau mice

Shuo Qian,Qin Huang,Wei Qian,Jianlan Gu,Dandan Chu,Wufei Dai,Nana Jin,Fei Liu

doi:10.18632/aging.101564

Abstract

Alternative splicing of tau exon 10 generates tau isoforms with three or four microtubule binding repeats, named 3R-tau and 4R-tau, respectively. Dysregulation of tau exon 10 splicing could cause neurofibrillary degeneration. Acetylation is one of the major post-translational protein modifications in the cell by attachment of the acetyl group to either the α-amino group of the N-terminus of proteins or to the ε-amino group of lysine residues. Sirt1, one member in mammalian Sirtuin family, deacetylates protein and is associated closely with age-related diseases including Alzheimer’s disease. However, the role of Sirt1 in tau exon 10 splicing remains elusive. In the present study, we determined the role of Sirt1 in tau exon 10 splicing. We found that activation of Sirt1 by resveratrol enhanced tau exon 10 inclusion, leading to 4R-tau expression. Sirt1 interacted with splicing factor 9G8, deacetylated it at Lys24, and suppressed its function in promoting tau exon 10 exclusion. Moreover, resveratrol improved learning and spatial memory in Htau mice. These findings suggest that Sirt1 may serve as a new drug target for Alzheimer’s Disease related tauopathies and resveratrol may be used to correct dysregulated tau exon 10 with 3R-tau > 4R-tau.

Highlights

Microtubule-associated protein tau promotes tubulin assembly and stabilizes microtubules structure
Resveratrol improved learning and spatial memory in Htau mice. These findings suggest that Sirt1 may serve as a new drug target for Alzheimer’s Disease related tauopathies and resveratrol may be used to correct dysregulated tau exon 10 with 3R‐tau > 4R‐tau
Almost half of tau gene mutations associated with FTDP-17T only disturb exon 10 splicing to disrupt the balance of 3R to 4R tau [4]

Summary

Introduction

Microtubule-associated protein tau promotes tubulin assembly and stabilizes microtubules structure. MAPT, is located on the long arm of human chromosome 17q21 [1]. There are six isoforms of tau proteins expressed in normal human brain by the alternative splicing of exons 2, 3, and/or 10 of tau premRNA [2]. Its alternative splicing generates tau isoforms with three or four microtubule binding repeats, called 3R- or 4R-tau [3]. Almost half of tau gene mutations associated with FTDP-17T (frontotemporal dementia with Parkinsonism linked to chromosome 17 and characterized by tau pathology) only disturb exon 10 splicing to disrupt the balance of 3R to 4R tau [4]. Maintaining the balance of 3R-tau and 4R-tau is important for normal brain function

Methods

Results

Conclusion