ARRIVE Guidelines are not applicable. No animal experiments performed.
Alternative polyadenylation and miR-34 family members regulate tau expression†
Article first published online: 18 SEP 2013
© 2013 International Society for Neurochemistry
Journal of Neurochemistry
Volume 127, Issue 6, pages 739–749, December 2013
How to Cite
J. Neurochem.(2013) 127, 739–749.
- Issue published online: 3 DEC 2013
- Article first published online: 18 SEP 2013
- Accepted manuscript online: 28 AUG 2013 11:11AM EST
- Manuscript Accepted: 26 AUG 2013
- Manuscript Revised: 22 AUG 2013
- Manuscript Received: 31 JUL 2013
- University of Southern Denmark
- Lundbeck Foundation
- NIH. Grant Number: GM007306
- 3′-untranslated region;
- Alzheimer's disease;
- gene regulation;
- MAPT ;
- neurodegenerative disease
Tau pathologically aggregates in Alzheimer's disease, and evidence suggests that reducing tau expression may be safe and beneficial for the prevention or treatment of this disease. We sought to examine the role of the 3′-untranslated region (3′-UTR) of human tau mRNA in regulating tau expression. Tau expresses two 3′-UTR isoforms, long and short, as a result of alternative polyadenylation. Using luciferase reporter constructs, we found that expression from these isoforms is differentially controlled in human neuroblastoma cell lines M17D and SH-SY5Y. Several microRNAs were computationally identified as candidates that might bind the long, but not short, tau 3′-UTR isoform. A hit from a screen of candidates, miR-34a, was subsequently shown to repress the expression of endogenous tau protein in M17D cells. Conversely, inhibition of endogenously expressed miR-34 family members leads to increased endogenous tau expression. In addition, through an unbiased screen of fragments of the human tau 3′-UTR using a luciferase reporter assay, we identified several other regions in the long tau 3′-UTR isoform that contain regulatory cis-elements. Improved understanding of the regulation of tau expression by its 3′-UTR may ultimately lead to the development of novel therapeutic strategies for the treatment of Alzheimer's disease and other tauopathies.
mRNA 3'-untranslated regions (3'-UTR) often regulate transcript stability or translation. Despite the centrality of the tau protein in Alzheimer's and other neurodegenerative diseases, the human tau 3'-UTR has been little studied. This report identifies regions of the tau 3'-UTR that influence expression and shows that microRNA (miR)-34a targets this 3'-UTR to lower expression, which is considered an important therapeutic goal.