MicroRNA-124 protects against focal cerebral ischemia via mechanisms involving Usp14-dependent REST degradation
2013 | journal article; research paper. A publication with affiliation to the University of Göttingen.
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Doeppner, T. R., et al. "MicroRNA-124 protects against focal cerebral ischemia via mechanisms involving Usp14-dependent REST degradation." Acta Neuropathologica, vol. 126, no. 2, 2013, pp. 251-265, doi: 10.1007/s00401-013-1142-5.
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- Authors
- Doeppner, T. R. ; Doehring, M.; Bretschneider, E. ; Zechariah, A.; Kaltwasser, B.; Müller, B.; Koch, J. C. ; Bähr, M. ; Hermann, D. M.; Michel, U.
- Abstract
- MicroRNAs (miRNAs) are highly conserved non-coding RNAs modulating gene expression via mRNA binding. Recent work suggests an involvement of miRNAs in cardiovascular diseases including stroke. As such, the brain-abundant miR-124 and its transcriptional repressor RE1-silencing transcription factor (REST) do not only have elementary roles in the developing and the adult brain, but also alter expression upon cerebral ischemia. However, the therapeutic potential of miR-124 against stroke and the mechanisms involved remain elusive. Here, we analyzed the therapeutic potential of ectopic miR-124 against stroke and its underlying mechanisms with regard to the interaction between miR-124 and REST. Our results show that viral vector-mediated miR-124 delivery increased the resistance of cultured oxygen-glucose-deprived cortical neurons in vitro and reduced brain injury as well as functional impairment in mice submitted to middle cerebral artery occlusion. Likewise, miR-124 induced enhanced neurovascular remodeling leading to increased angioneurogenesis 8 weeks post-stroke. While REST abundance increased upon stroke, the increase was prevented by miR-124 despite a so far unknown negative feedback loop between miR-124 and REST. Rather, miR-124 decreased the expression of the deubiquitinating enzyme Usp14, which has two conserved miR-124-binding sites in the 3'UTR of its mRNA, and thereby mediated reduced REST levels. The down-regulation of REST by miR-124 was also mimicked by the Usp14 inhibitor IU-1, suggesting that miR-124 promotes neuronal survival under ischemic conditions via Usp14-dependent REST degradation. Ectopic miR-124 expression, therefore, appears as an attractive and novel tool in stroke treatment, mediating neuroprotection via a hitherto unknown mechanism that involves Usp14-dependent REST degradation.
- Issue Date
- 2013
- Journal
- Acta Neuropathologica
- ISSN
- 0001-6322
- eISSN
- 1432-0533
- Language
- English