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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

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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 1

miR-219 is downregulated in autopsy brain tissue from AD and TPD patients.

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miR-219 is downregulated in autopsy brain tissue from AD and TPD patient...
(A) Pie charts showing the proportion of RNA-sequencing reads mapping to noncoding RNA subgroups (average in each comparison group). piRNA, piwi-interacting RNA; snoRNA, small nucleolar RNA; tRNA, transfer RNA. (B) Correlations of the normalized read frequencies of all detected miRNAs between representative subjects and the average from all profiles demonstrate a high degree of correlation. (C) Heatmap diagram with unsupervised hierarchical clustering showing changes in the levels of the most significant miRNAs identified in AD (n = 6) and TPD (n = 3) brain tissue samples relative to those of controls (n = 7). Statistical analysis was performed using 1-way ANOVA (P < 0.05, unadjusted). Data are shown as a pseudocolored heatmap (log2-transformed relative expression values of the normalized read frequency). (D) qPCR confirmed decreased levels of miR-219 in TPD (n = 19) and AD (n = 7) brain tissue samples compared with those of controls (n = 20). SNORD24 levels were used for normalization. **P ≤ 0.01 by 2-tailed Student’s t test.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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