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Chronically stressed or stress-preconditioned neurons fail to maintain stress granule assembly

Shelkovnikova, Tatyana, Dimasi, Pasquale, Kukharsky, Michail, An, Haiyan, Quintiero, Annamaria, Schirmer, Claire, Buée, Luc, Galas, Marie-Christine and Buchman, Vladimir 2017. Chronically stressed or stress-preconditioned neurons fail to maintain stress granule assembly. Cell Death and Disease 8 , e2788. 10.1038/cddis.2017.199

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Abstract

Dysregulation of stress granules (SGs) and their resident proteins contributes to pathogenesis of a number of (neuro)degenerative diseases. Phosphorylation of eIF2α is an event integrating different types of cellular stress and it is required for SG assembly. Phosphorylated eIF2α (p-eIF2α) is upregulated in the nervous system in some neurodegenerative conditions. We found that increasing p-eIF2α level by proteasomal inhibition in cultured cells, including mouse and human neurons, prior to a SG-inducing stress (‘stress preconditioning’), limits their ability to maintain SG assembly. This is due to upregulation of PP1 phosphatase regulatory subunits GADD34 and/or CReP in preconditioned cells and early decline of p-eIF2α levels during subsequent acute stress. In two model systems with constitutively upregulated p-eIF2α, mouse embryonic fibroblasts lacking CReP and brain neurons of tau transgenic mice, SG formation was also impaired. Thus neurons enduring chronic stress or primed by a transient mild stress fail to maintain p-eIF2α levels following subsequent acute stress, which would compromise protective function of SGs. Our findings provide experimental evidence on possible loss of function for SGs in certain neurodegenerative diseases.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Subjects: Q Science > Q Science (General)
R Medicine > R Medicine (General)
Publisher: Nature Publishing Group
ISSN: 2041-4889
Date of First Compliant Deposit: 27 April 2017
Date of Acceptance: 4 April 2017
Last Modified: 25 Sep 2019 23:27
URI: http://orca.cf.ac.uk/id/eprint/99940

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