Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tau
Ismael Santa-Maria, … , Brian D. McCabe, John F. Crary
Ismael Santa-Maria, … , Brian D. McCabe, John F. Crary
Published January 9, 2015
Citation Information: J Clin Invest. 2015;125(2):681-686. https://doi.org/10.1172/JCI78421.
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Brief Report Neuroscience

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

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

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Figure 2

In vivo regulation of tau toxicity and expression by miR-219.

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In vivo regulation of tau toxicity and expression by miR-219. (A and B) ...
(A and B) Coexpression of miR-219 partially suppressed the human tau–induced rough eye phenotype compared with that seen in the scrambled miR-219. (C and D) Coexpression of the miR-219 sponge with human tau exacerbated the phenotype compared with that observed in the scrambled sponge. Scale bar: 100 μm. (E) Semiquantitative assessments of the rough eye phenotype (n = 38/group). (F) miR-219 recognition element in the tau 3′-UTR. (G) Schematic illustrating regulation of tau by miR-219 and de-repression with the sponge. (H and I) Quantitative immunoblot of extracts from flies expressing miR-219 in the brain revealed decreased Drosophila tau protein levels compared with those detected in the scrambled control. Expression of the miR-219 sponge shows increased tau protein levels compared with those in the scrambled control (noncontiguous from the same gel). (J) qPCR shows that the tau mRNA levels were unchanged in the miR-219–expressing flies, but there was an increase in tau mRNA levels in flies expressing the miR-219 sponge compared with that observed in the scrambled control. (K) Flies that coexpress miR-219 and luciferase fused to the human tau 3′-UTR showed reduced activity compared with that seen in the scrambled control. Conversely, the miR-219 sponge significantly increased 3′-UTR activity compared with that in the scrambled control. Flies expressing a GAPDH 3′-UTR fused to luciferase were used for normalization. Data are representative of 3 experiments. *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001 by 2-tailed Student’s t test; ****P ≤ 0.0001 by Mann-Whitney U test.