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Chronically stressed or stress-preconditioned neurons fail to maintain stress granule assembly
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DOI：10.1038/cddis.2017.199.png)
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Abstract
En 中文
Dysregulation of stress granules (SGs) and their resident proteins contributes to pathogenesis of a number of (neuro) degenerative diseases. Phosphorylation of eIF2 alpha is an event integrating different types of cellular stress and it is required for SG assembly. Phosphorylated eIF2 alpha (p-eIF2 alpha) is upregulated in the nervous system in some neurodegenerative conditions. We found that increasing p-eIF2 alpha 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-eIF2 alpha levels during subsequent acute stress. In two model systems with constitutively upregulated p-eIF2 alpha, 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-eIF2 alpha 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.
Keywords:
NEURODEGENERATIVE DISEASES
TRANSLATIONAL REPRESSION
SELECTIVE-INHIBITION
AGGREGATION
MUTATIONS
PROTEINS
TAU
SUPPRESSION
PROTECTS
REVEALS
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