title: RESP18 is involved in the cytotoxicity of dopaminergic neurotoxins in MN9D cells.
abstract: RESP18 (Regulated endocrine-specific protein, 18 kDa) was first identified as a dopaminergic drugs-regulated intermediate pituitary transcript. RESP18 protein is a unique endoplasmic reticulum (ER) resident protein. Its functions in the brain especially in the nervous system disorders remain unknown. ER stress (ERS) has been proved to be one of the important pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD). Here, we explored the association of RESP18 and ERS in cell models of PD. Dopaminergic neurotoxin 1-methyl-4-phenyl-pyridinium ion (MPP⁺), 6-hydroxydopamine (6-OHDA), and rotenone evoked dramatic MN9D cell death. The transcriptional expressions of RESP18 and two ERS markers--binding immunoglobulin protein/glucose-regulated protein 78 (BiP/GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP) manifested differential changes in MN9D cells treated with MPP⁺, 6-OHDA, and rotenone. The RESP18 protein levels increased in MPP⁺ and 6-OHDA-treated cells, but did not change in the cells treated with rotenone, while the protein levels of ER molecular chaperone heat shock protein 90 kDa beta member 1/glucose-regulated protein 94 (HSP90B1/GRP94) and BiP in the cells were up-regulated by MPP⁺ and 6-OHDA, respectively. Salubrinal, an ERS inhibitor, significantly reduced MPP⁺ and 6-OHDA-induced cell death. Moreover, ERS inducer--thapsigargin and tunicamycin, decreased the expression of RESP18, which is different from the changes of BiP, GRP94, and CHOP. Silencing RESP18 expression with Lenti-shRNA alleviated MPP⁺-induced cell death, while over-expression of RESP18 resulted in aggravated cell death induced by MPP⁺ and 6-OHDA. Taken together, our results suggest that RESP18 is involved in the cytotoxicity of dopaminergic neurotoxins.
authors: State Key Laboratory of Medical Neurobiology, Shanghai Medical College and Institutes of Brain Science, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
authors: Yufang
authors: Y
authors: Huang
authors: Jing
authors: J
authors: Xu
authors: Min
authors: M
authors: Liang
authors: Xiaoqi
authors: X
authors: Hong
authors: Haiyun
authors: H
authors: Suo
authors: Jie
authors: J
authors: Liu
authors: Mei
authors: M
authors: Yu
authors: Fang
authors: F
authors: Huang
mesh_terms: D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D015259:Dopamine Agents / Q000633:toxicity*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*
chemical_list: D015259:Dopamine Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D009419:Nerve Tissue Proteins; C086381:regulated endocrine secretory protein 18