Trehalose inhibits H₂O₂-induced autophagic death in dopaminergic SH-SY5Y cells via mitigation of ROS-dependent endoplasmic reticulum stress and AMPK activation

Abstract

Autophagy is a catabolic process to maintain intracellular homeostasis via removal of cytoplasmic macromolecules and damaged cellular organelles through lysosome-mediated degradation. Trehalose is often regarded as an autophagy inducer, but we reported previously that it could prevent ischemic insults-induced autophagic death in neurons. Thus, we further investigated in this study whether trehalose could protect human dopaminergic SH-SY5Y cells against H2O2-induced lethal autophagy. We found pretreatment with trehalose not only prevented H2O2-induced death in SH-SY5Y cells, but also reversed H2O2-induced upregulation of LC3II, Beclin1 and ATG5 and downregulation of p62. Then, we proved that either autophagy inhibitor 3MA or genetic knockdown of ATG5 prevented H2O2-triggered death in SH-SY5Y cells. These indicated that trehalose could inhibit H2O2-induced autophagic death in SH-SY5Y cells. Further, we found that trehalose inhibited H2O2-induced AMPK activation and endoplasmic reticulum (ER) stress. Moreover, inhibition of AMPK activation with compound C or alleviation of ER stress with chemical chaperone 4-PBA obviously attenuated H2O2-induced changes in autophagy-related proteins. Notably, we found that trehalose inhibited H2O2-induced increase of intracellular ROS and reduction in the activities of CAT and SOD. Consistently, our data revealed as well that mitigation of intracellular ROS levels with antioxidant NAC markedly attenuated H2O2-induced AMPK activation and ER stress. Therefore, we demonstrated in this study that trehalose prevented H2O2-induced autophagic death in SH-SY5Y cells via mitigation of ROS-dependent endoplasmic reticulum stress and AMPK activation.

Brown planthopper infestations alter sugar metabolism in the rice plant as well as brown planthopper

“…This was likely caused by increased Tre activities. In addition, trehalose restrained the H 2 O 2 ‐induced increase of intracellular ROS (Gao et al, 2018), indicating that trehalose level changes are likely related to response to biotic stress. Extracellular trehalose is potentially a signal of insect attack (Singh et al, 2011).…”

Nicotine Prevents Oxidative Stress-Induced Hippocampal Neuronal Injury Through α7-nAChR/Erk1/2 Signaling Pathway

“…Evidence further demonstrated that H 2 O 2 -induced mitochondrial membrane depolarization, swelling, and fragmentation could be due to the motility of mitochondria accompanied with mitochondrial elongation (Debattisti et al, 2017 ). Moreover, evidence showed that H 2 O 2 could induce autophagic death in dopaminergic SY5Y cells through ROS-dependent endoplasmic reticulum stress and AMPK activation (Gao Z. et al, 2018 ). Therefore, it is of importance to identify a mechanism that exerts neuroprotective effects against oxidative injury.…”

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.…”