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.
Highlights
Stress granules (SGs) are cytoplasmic RNA–protein macrocomplexes that form as a normal cellular response to a moderate-to-severe stress and serve to protect cellular RNAs from degradation until translation can be safely restored.[1]
SGs are believed to be protective under stress because they guard sensitive transcripts, and because they participate in signaling events including anti-apoptotic signals,[2,3,4] favor translation of molecular chaperones/other cytoprotective proteins[1] and help adjusting cellular translation rates to accumulation of misfolded proteins that accompany some types of stress.[5]
A growing list of SG proteins have been implicated in neurodegenerative conditions, primarily amyotrophic lateral sclerosis (ALS) and a related condition, frontotemporal lobar degeneration (FTLD); many of them are modified by mutations in the encoding genes in these diseases
Summary
Stress granules (SGs) are cytoplasmic RNA–protein macrocomplexes that form as a normal cellular response to a moderate-to-severe stress and serve to protect cellular RNAs from degradation until translation can be safely restored.[1]. SG formation is tightly linked to phosphorylation of the translation initiation factor eIF2α The latter event depletes the eIF2/tRNAiMet/GTP ternary complex required for translation initiation causing translational arrest, polysome disassembly and eventually SG assembly.[13] Increased levels of p-eIF2α have been detected in the nervous system of patients with some neurodegenerative conditions such as Alzheimer’s disease and prion disorders,[14,15,16] as well as animal models of neurodegeneration.[17,18,19,20] SG formation in most cases requires elevated p-eIF2α levels, it is still not clear how SG formation would be modulated by the presence of increased ‘basal’ (pre-stress) p-eIF2α levels. Short-term or chronic elevation of p-eIF2α levels, when coupled with upregulation of its phosphatase, impairs the ability of cells, including neurons in vitro and in vivo, to maintain SG assembly following a SG-inducing stress
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