Santa-María, IsmaelAlaniz, Maria E.Renwick, NeilCela, CarolinaFulga, Tudor A.Van Vactor, DavidTuschl, ThomasClark, Lorraine N.Shelanski, Michael L.McCabe, Brian D.Crary, John F.2025-01-122025-01-122015Santa-Maria, I., Alaniz, M..E, Renwick, N., et al. Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tau.The Journal of Clinical Investigation, Vol. 125, Núm. 2, pp. 681-6.0021-9738https://hdl.handle.net/10641/5573Tau 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.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/journal articleopen access10.1172/JCI78421