Modulation of p-eIF2α cellular levels and stress granule assembly/disassembly by trehalose

Abstract

Stress granules (SGs) are an important component of cellular stress response. Compromised assembly of SGs as well as their premature or delayed disassembly affect physiology and survival of cells under stress or during recovery from stress. Consequently, abnormal turnover of SGs has been implicated in the development of various pathologies, including neurodegeneration. We found that pretreatment of cells with a natural disaccharide trehalose, a known autophagy enhancer, delays SG assembly and facilitates their premature post-stress disassembly. Mechanistically, the effect of trehalose on SGs is mediated via the p-eIF2α rather than autophagosome pathway. Trehalose increases pre-stress levels of p-eIF2α and its phosphatase subunits and promotes post-stress translational recovery. Upon prolonged treatment, trehalose impairs basal translation affecting production of transiently expressed proteins. Early translational recovery and SG disassembly induced by trehalose pretreatment can sensitise cells to stress and impair survival. Our study has important implications for the use of trehalose in studies of autophagic clearance of misfolded proteins and for targeting SGs as a possible therapeutic approach in neurodegenerative and other diseases.

Endoplasmic reticulum stress remodels alveolar bone formation after tooth extraction

“…This finding is consistent with a previous study reporting that specific inhibition of ER stress blocked apoptosis and decreased mineralization induced by either glucocorticoid or ER stress inducer Tm in OB-6 cells or POBs. 18 ALP and Runx2 expression were weakest under the action of Tm, but p-eIF2α/eIF2α expression was highest in this context; thus, the increase in the basal p-eIF2α level by Tm indicates that the treated cells undergo some sort of stress, 37 and excessive ER stress inhibits osteogenic differentiation and causes apoptosis 38 (Figure 5). As the concentration of salubrinal increased, the level of p-eIF2α/eIF2α F I G U R E 3 Suppressing ER stress could accelerate bone formation.…”

Mechanism of neuroprotection by trehalose: controversy surrounding autophagy induction

“…Prolonged accumulation of the stress granules may lead to increased protein aggregation and the pathogenesis of neurodegenerative diseases. Trehalose efficiently promoted the stress granule disassembly via the p-eIF2α pathway, suggesting that neuroprotective effects of trehalose may include the regulation of the stress granules 87 .…”

Beneficial Effects of Trehalose on Striatal Dopaminergic Deficits in Rodent and Primate Models of Synucleinopathy in Parkinson’s Disease

“…Even if trehalose is an autophagy enhancer it is difficult to explain how trehalose could produce neuroprotection in a toxin-lesioned model of PD, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Sarkar et al, 2014), without additional actions. Several other effects of trehalose, independent of autophagy, have also been suggested to confer the neuroprotective effects of trehalose, including being a chemical chaperone (Crowe, 2007;Sarkar et al, 2014), downregulation of poly(ADP-ribose) polymerase (Spina-Purrello et al, 2010), regulation of stress granules (Dimasi et al, 2017), anti-inflammatory actions (Echigo et al, 2012;Pagliassotti et al, 2017;Mirzaie et al, 2018), inducer of neurotrophic factors (Perucho et al, 2016;Portbury et al, 2017a,b), and reduction of oxidative stress (Gao et al, 2018;Mizunoe et al, 2018). Any one of these mechanisms, or more likely a combination of several of these mechanisms, may be responsible for the neuroprotective effects of trehalose.…”