Effects of homocysteine-induced endoplasmic reticulum protein on endoplasmic reticulum stress, autophagy, and neuronal apoptosis following intracerebral hemorrhage

Hui Wu; Jinglei Wang; Maohong Cao; Jingjing Liang; Dan Wu; Xingxing Gu; Kaifu Ke

doi:10.1016/j.ibror.2020.08.004

Effects of homocysteine-induced endoplasmic reticulum protein on endoplasmic reticulum stress, autophagy, and neuronal apoptosis following intracerebral hemorrhage

IBRO Rep. 2020 Aug 27:9:207-217. doi: 10.1016/j.ibror.2020.08.004. eCollection 2020 Dec.

Authors

Hui Wu¹, Jinglei Wang¹, Maohong Cao², Jingjing Liang², Dan Wu³, Xingxing Gu⁴, Kaifu Ke²

Affiliations

¹ Nantong University, Nantong, Jiangsu Province, People's Republic of China.
² Department of Neurology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, People's Republic of China.
³ Department of Neurology, Tongzhou People's Hospital, Nantong, Jiangsu Province, People's Republic of China.
⁴ Jiangsu Key Laboratory of Neuroregeneration, Department of Neuronscience, Nantong University, Nantong, Jiangsu Province, People's Republic of China.

Abstract

Intracerebral hemorrhage (ICH) is defined as bleeding into the brain parenchyma with a high mortality and morbidity rate. Unfortunately, it remains an unresolved medical problem. Therefore, it is necessary to find ways to reduce cellular apoptosis after ICH. Homocysteine-induced endoplasmic reticulum protein (HERP), a 54 kD transmembrane protein, is an early stress response protein encoded by ubiquitin-like domain member 1 (Herpud1) gene. In the present work, our group investigated the role of HERP after ICH and hemin stimulation, HERP expression was examined in mouse and primary cortical neurons after ICH and hemin stimulation by western blot and Immunofluorescent labeling. Using shRNA-HERP plasmid and recombinant adenovirus, we also investigated how HERP affected neuronal apoptosis after ICH and hemin stimulation. In addition, behavioral evaluation was used to ensure our models' success. In vivo and vitro studies, the expression of HERP was increased following ICH and hemin-exposed primary cortical neurons. HERP depletion activated the endoplasmic reticulum (ER) stress pathway and apoptosis in hemin-exposed primary cortical neurons, but inhibited autophagy in hemin-exposed primary cortical neurons. Overexpression of HERP inhibited the ER stress pathway and apoptosis, but activated autophagy in hemin-exposed primary cortical neurons. Consequently, we confirm that HERP plays a protective role in ICH model.

Keywords: Apoptosis; Autophagy; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum-associated protein degradation; Endoplasmic reticulum stress; HERP, homocysteine-induced endoplasmic reticulum protein; Herpud1, homocysteine-inducible and ER-stress-inducible, ubiquitin-like domain member 1; Homocysteine-induced endoplasmic reticulum protein; ICH, intracerebral hemorrhage; Intracerebral hemorrhage; Mice; TM, tunicamycin; TUDCA, tauroursodeoxycholic acid.