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

Tatyana Shelkovnikova (1) , Pasquale Dimasi (1) , Michail Kukharsky (1) , Haiyan An (1) , Annamaria Quintiero (1) , Claire Schirmer (2) , Luc Buée (2) , Marie-Christine Galas (2) , Vladimir Buchman (1)

1 Cardiff University
2 Alzheimer & Tauopathies [JPArc]

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

Domaines: Neurobiologie; Médecine humaine et pathologie

Tatyana Shelkovnikova, Pasquale Dimasi, Michail Kukharsky, Haiyan An, Annamaria Quintiero, et al.. Chronically stressed or stress-preconditioned neurons fail to maintain stress granule assembly. Cell Death and Disease, 2017, 8 (5), pp.e2788. ⟨10.1038/cddis.2017.199⟩. ⟨hal-03093247⟩