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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.

SUBMITTER: Santa-Maria I

PROVIDER: S-EPMC4319412 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tau.

Santa-Maria Ismael I Alaniz Maria E ME Renwick Neil N Cela Carolina C Fulga Tudor A TA Van Vactor David D Tuschl Thomas T Clark Lorraine N LN Shelanski Michael L ML McCabe Brian D BD Crary John F JF

The Journal of clinical investigation 20150109 2

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 ...[more]

PMID: 25574843

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Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tau.

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Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tau.

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