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Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tau.

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.
AuthorsIsmael 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
JournalThe Journal of clinical investigation (J Clin Invest) Vol. 125 Issue 2 Pg. 681-6 (Feb 2015) ISSN: 1558-8238 [Electronic] United States
PMID25574843 (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)

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