title: 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.
authors.forename: Ismael
authors.initials: I
authors.lastname: Santa-Maria
authors.forename: Maria E
authors.initials: ME
authors.lastname: Alaniz
authors.forename: Neil
authors.initials: N
authors.lastname: Renwick
authors.forename: Carolina
authors.initials: C
authors.lastname: Cela
authors.forename: Tudor A
authors.initials: TA
authors.lastname: Fulga
authors.forename: David
authors.initials: D
authors.lastname: Van Vactor
authors.forename: Thomas
authors.initials: T
authors.lastname: Tuschl
authors.forename: Lorraine N
authors.initials: LN
authors.lastname: Clark
authors.forename: Michael L
authors.initials: ML
authors.lastname: Shelanski
authors.forename: Brian D
authors.initials: BD
authors.lastname: McCabe
authors.forename: John F
authors.initials: JF
authors.lastname: Crary
mesh_terms: D020413:3' Untranslated Regions; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D004331:Drosophila melanogaster; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis; D016875:tau Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; C578248:MIRN219 microRNA, human; D035683:MicroRNAs; D016875:tau Proteins