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

ABSTRACT: Dysregulation of stress granules (SGs) and their resident proteins contributes to pathogenesis of a number of (neuro)degenerative diseases. Phosphorylation of eIF2? is an event integrating different types of cellular stress and it is required for SG assembly. Phosphorylated eIF2? (p-eIF2?) is upregulated in the nervous system in some neurodegenerative conditions. We found that increasing p-eIF2? 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? levels during subsequent acute stress. In two model systems with constitutively upregulated p-eIF2?, 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? 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.

SUBMITTER: Shelkovnikova TA 

PROVIDER: S-EPMC5520719 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature