Salsolinol causing parkinsonism activates endoplasmic reticulum-stress signaling pathways in human dopaminergic SK-N-SH cells.
The endoplasmic reticulum (ER) is a small intracellular organelle to which one-third of cellular proteins are translocated after translation and post-translational modification, folding and the formation of a three- or four-dimensional structure. ER also has a role in the transportation of proteins to other intracellular organelles, the cell surface or the outer space of the cell membrane. Thus, ER is an important intermediate which maintains intracellular homeostasis through complex control systems. Once these control systems are disrupted, serious disturbances occur. Many neurodegenerative diseases including Parkinson's disease involve aggregation and deposition of misfolded proteins such as alpha-synuclein. Endogenously occurring neurotoxins such as Salsolinol and 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) causing Parkinsonism may foster misfolded proteins and bring forth ER stress in dopaminergic neurons. In the present study we examined translational changes fostered by ER stress and mediated by the Parkinsonian endogenous neurotoxins, salsolinol and 1BnTIQ, in dopaminergic cell line. Treatment with salsolinol and 1BnTIQ induced several genes involved in ER stress and unfolded protein response (UPR), such as ER chaperones and GADD153 (CHOP). Immunoblotting confirmed phosphorylation of the key endoplasmic reticulum stress kinase PERK (PKR-like-ER kinase) and eIF2alpha and induction of their downstream targets such as Bip and GADD153. These findings suggest a widespread involvement of ER stress and unfolded protein response in the pathophysiology of Parkinson's disease.
Kheradpezhouh
Mohsen
M
Department of Pharmacology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, N Dakota 58202, USA.
Shavali
Shaik
S
Ebadi
Manuchair
M
D015153:Blotting, Western / Q000379:methods; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005455:Fluorescent Antibody Technique / Q000379:methods; D006360:Heat-Shock Proteins; D006801:Humans; D007546:Isoquinolines / Q000633:toxicity*; D018832:Molecular Chaperones; D009447:Neuroblastoma; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D013312:Stress, Physiological / Q000139:chemically induced / Q000378:metabolism*; D044005:Tetrahydroisoquinolines / Q000633:toxicity; D013997:Time Factors; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D004298:Dopamine; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D007546:Isoquinolines; D018832:Molecular Chaperones; D044005:Tetrahydroisoquinolines; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D019892:eIF-2 Kinase; C497249:DDIT3 protein, human; C036617:salsolinol; C084924:1,2,3,4-tetrahydro-1-(phenylmethyl)isoquinoline