Chronically stressed or stress-preconditioned neurons fail to maintain stress granule assembly. Shelkovnikova, T. A., Dimasi, P., Kukharsky, M. S., An, H., Quintiero, A., Schirmer, C., Buée, L., Galas, M., & Buchman, V. L. Cell Death & Disease, 8(5):e2788, May, 2017.
doi  abstract   bibtex   
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, before 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.
@article{shelkovnikova_chronically_2017,
	title = {Chronically stressed or stress-preconditioned neurons fail to maintain stress granule assembly},
	volume = {8},
	issn = {2041-4889},
	doi = {10.1038/cddis.2017.199},
	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, before 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.},
	language = {eng},
	number = {5},
	journal = {Cell Death \& Disease},
	author = {Shelkovnikova, Tatyana A. and Dimasi, Pasquale and Kukharsky, Michail S. and An, Haiyan and Quintiero, Annamaria and Schirmer, Claire and Buée, Luc and Galas, Marie-Christine and Buchman, Vladimir L.},
	month = may,
	year = {2017},
	pmid = {28492545},
	pmcid = {PMC5520719},
	keywords = {Humans, Neurons, Animals, Nerve Tissue Proteins, Mice, Mice, Knockout, Cytoplasmic Granules, Stress, Physiological},
	pages = {e2788}
}

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