Abstract
In the past decade, several groups have reported that microRNAs (miRNAs) can participate in the regulation of tau protein at different levels, including its expression, alternative splicing, phosphorylation, and aggregation. These observations are significant, since the abnormal regulation and deposition of tau is associated with nearly 30 neurodegenerative disorders. Interestingly, miRNA profiles go awry in tauopathies such as Alzheimer's disease, progressive supranuclear palsy, and frontotemporal dementia. Understanding the role and impact of miRNAs on tau biology could therefore provide important insights into disease risk, diagnostics, and perhaps therapeutics. In this Perspective article, we discuss recent advances in miRNA research related to tau. While proof-of-principle studies hold promise, physiological validation remains limited. To help fill this gap, we describe herein a pure tauopathy mouse model deficient for the miR-132/212 cluster. This miRNA family is strongly downregulated in human tauopathies and shown to regulate tau in vitro and in vivo. No significant differences in survival, motor deficits or body weight were observed in PS19 mice lacking miR-132/212. Age-specific effects were seen on tau expression and phosphorylation but not aggregation. Moreover, various miR-132/212 targets previously implicated in tau modulation were unaffected (GSK-3β, Foxo3a, Mapk1, p300) or, unexpectedly, reduced (Mapk3, Foxo1, p300, Calpain 2) in miR-132/212-deficient PS19 mice. These observations highlight the challenges of miRNA research in living models, and current limitations of transgenic tau mouse models lacking functional miRNA binding sites. Based on these findings, we finally recommend different strategies to better understand the role of miRNAs in tau physiology and pathology.
Highlights
Tauopathies comprise a group of ∼30 neurodegenerative disorders characterized by the pathological accumulation of hyperphosphorylated and insoluble tau in neurons and/or glia [1]
The most prevalent tauopathy is Alzheimer’s disease (AD), where tau aggregates into neurofibrillary tangles (NFTs) in conjunction with amyloid-β (Aβ) plaques [3]
Most miRNA literature is based on indirect or artificial paradigms that await physiological validation. In this Perspective article, we provide an overview of advances related to the regulation of tau by miRNAs
Summary
Tauopathies comprise a group of ∼30 neurodegenerative disorders characterized by the pathological accumulation of hyperphosphorylated and insoluble tau in neurons and/or glia [1]. MicroRNAs and Tauopathies transcript undergoes different steps of regulation including finetuning of expression, alternative splicing of exons 2, 3, and 10, and multiple levels of phosphorylation [1]. These modifications play a central role in tau function related to the binding and stabilization of microtubules [2]. The most common and straightforward approach is introducing a mutation within the miRNA target site (in particular the seed sequence) to inhibit miRNA:mRNA binding and gene expression regulation This strategy is quite challenging in vivo with only one known report in the mammalian brain [10], unrelated to tau. An important step will be to identify the functional miRNA:mRNA pairs within the biological networks in brain cells
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