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Endoplasmic reticulum stress-mediated upregulation of miR-29a enhances sensitivity to neuronal apoptosis.

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posted on 22.11.2019 by Katie Nolan, Franziska Walter, Liam P. Tuffy, Simone Poeschel, Ross Gallagher, Stefan Haunsberger, Isabella Bray, Raymond L. Stallings, Caoimhín G. Concannon, Jochen HM Prehn

Disturbance of homeostasis within the endoplasmic reticulum (ER) lumen leads to the accumulation of unfolded and misfolded proteins. This results in the activation of an evolutionary conserved stress response termed ER stress that, if unresolved, induces apoptosis. Previously the Bcl-2 homology domain 3-Only Protein Puma was identified as a mediator of ER stress-induced apoptosis in neurons. In the search of alternative contributors to ER stress-induced apoptosis, a downregulation of the anti-apoptotic Bcl-2 family protein Mcl-1 was noted during ER stress in both mouse cortical neurons and human SH-SY5Y neuroblastoma cells. Downregulation of Mcl-1 was associated with an upregulation of microRNA-29a (miR-29a) expression, and subsequent experiments showed that miR-29a targeted the 3'-untranslated region of the anti-apoptotic Bcl-2 family protein, Mcl-1. Inhibition of miR-29a expression using sequence-specific antagomirs or the overexpression of Mcl-1 decreased cell death following tunicamycin treatment, while gene silencing of Mcl-1 increased cell death. miR-29a did not alter the signalling branches of the ER stress response, rather its expression was controlled by the ER stress-induced transcription factor activating-transcription-factor-4 (ATF4). The current data demonstrate that the ATF4-mediated upregulation of miR-29a enhances the sensitivity of neurons to ER stress-induced apoptosis.

Funding

Science Foundation Ireland. Health Research Board.

History

Comments

"This is the peer reviewed version of the following article: European Journal of Neuroscience. 2016;43(5):640-52. Endoplasmic reticulum stress-mediated upregulation of miR-29a enhances sensitivity to neuronal apoptosis. Nolan K, Walter F, Tuffy LP, Poeschel S, Gallagher R, Haunsberger S, Bray I, Stallings RL, Concannon CG, Prehn JH, which has been published in final form at DOI: 10.1111/ejn.13160. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving."

Published Citation

Nolan K, Walter F, Tuffy LP, Poeschel S, Gallagher R, Haunsberger S, Bray I, Stallings RL, Concannon CG, Prehn JH. Endoplasmic reticulum stress-mediated upregulation of miR-29a enhances sensitivity to neuronal apoptosis. European Journal of Neuroscience. 2016;43(5):640-52.

Publication Date

01/03/2016

Publisher

Blackwell Science

PubMed ID

26750440

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