Abstract |
Tau is a highly abundant and multifunctional brain protein that accumulates in neurofibrillary tangles (NFTs), most commonly in Alzheimer's disease (AD) and primary age-related tauopathy. Recently, microRNAs ( miRNAs) have been linked to neurodegeneration; however, it is not clear whether miRNA dysregulation contributes to tau neurotoxicity. Here, we determined that the highly conserved brain miRNA miR-219 is downregulated in brain tissue taken at autopsy from patients with AD and from those with severe primary age-related tauopathy. In a Drosophila model that produces human tau, reduction of miR-219 exacerbated tau toxicity, while overexpression of miR-219 partially abrogated toxic effects. Moreover, we observed a bidirectional modulation of tau levels in the Drosophila model that was dependent on miR-219 expression or neutralization, demonstrating that miR-219 regulates tau in vivo. In mammalian cellular models, we found that miR-219 binds directly to the 3'-UTR of the tau mRNA and represses tau synthesis at the post-transcriptional level. Together, our data indicate that silencing of tau by miR-219 is an ancient regulatory mechanism that may become perturbed during neurofibrillary degeneration and suggest that this regulatory pathway may be useful for developing therapeutics for tauopathies.
|
Authors | Ismael Santa-Maria, Maria E Alaniz, Neil Renwick, Carolina Cela, Tudor A Fulga, David Van Vactor, Thomas Tuschl, Lorraine N Clark, Michael L Shelanski, Brian D McCabe, John F Crary |
Journal | The Journal of clinical investigation
(J Clin Invest)
Vol. 125
Issue 2
Pg. 681-6
(Feb 2015)
ISSN: 1558-8238 [Electronic] United States |
PMID | 25574843
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
|
Chemical References |
- 3' Untranslated Regions
- MIRN219 microRNA, human
- MicroRNAs
- tau Proteins
|
Topics |
- 3' Untranslated Regions
- Alzheimer Disease
(genetics, metabolism, pathology)
- Animals
- Disease Models, Animal
- Drosophila melanogaster
- Humans
- MicroRNAs
(genetics, metabolism)
- Protein Biosynthesis
- tau Proteins
(biosynthesis, genetics)
|