Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 125, Issue 2, Pages 681-686Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI78421
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Funding
- NIH [P30AG036453, K08NS072235, R01CA159227, R01MH080442, R01N5069695, P50AG08702, R01AG037212, P01AG07232, R01NS042859, P30AG028383, P50AG05131, U24NS072026, P30AG19610]
- Alzheimer's Association [NIRG-11-204450]
- Louis V. Gerstner Jr. Foundation
- Howard Hughes Medical Institute (HHMI)
- BrightFocus Foundation
- Arizona Department of Health Services
- Arizona Biomedical Research Commission
- Michael J. Fox Foundation
- Medical Research Council [G0902418] Funding Source: researchfish
- MRC [G0902418] Funding Source: UKRI
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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.
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