Research Paper Volume 10, Issue 9 pp 2498—2510
Sirt1 enhances tau exon 10 inclusion and improves spatial memory of Htau mice
- 1 Department of Biochemistry and Molecular Biology, Medical School, Nantong University, Nantong, Jiangsu 226001, P. R. China
- 2 Jiangsu Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, P. R. China
- 3 Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA
received: July 24, 2018 ; accepted: September 14, 2018 ; published: September 22, 2018 ;https://doi.org/10.18632/aging.101564
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Copyright: Qian et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.