title: Sigma-1 receptor agonist PRE084 is protective against mutant huntingtin-induced cell degeneration: involvement of calpastatin and the NF-κB pathway.
abstract: Alterations in mitochondria and increased oxidative stress are associated with the disease progression in Huntington's disease (HD). Endoplasmic reticulum (ER) stress and oxidative damage are linked through the close communication between the ER and mitochondria. Sigma-1 receptor (Sig-1R) is a chaperone protein in the ER that is involved in ER stress regulation, but little is known about its role in HD or the mechanisms for cell protection. Here we show that the Sig-1R agonist, PRE084 increases cell survival and counteracts the deleterious effects caused by N-terminal mutant huntingtin proteins in neuronal PC6.3 cells. Particularly, PRE084 increased the levels of cellular antioxidants by activating the NF-κB pathway that is compromised by the expression of mutant huntingtin proteins. These results show that the Sig-1R agonist has beneficial effects in models of HD and that compounds affecting the Sig-1R may be promising targets for future drug development in HD.
authors.affiliation: Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Biomedicum Helsinki, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Hyrskyluoto
authors.forename: I
authors.initials: I
authors.lastname: Pulli
authors.forename: K
authors.initials: K
authors.lastname: Törnqvist
authors.forename: T Huu
authors.initials: TH
authors.lastname: Ho
authors.forename: L
authors.initials: L
authors.lastname: Korhonen
authors.forename: D
authors.initials: D
authors.lastname: Lindholm
mesh_terms: D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D000071058:Huntingtin Protein; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D017480:Receptors, sigma / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D020169:Caspases; D000071058:Huntingtin Protein; D009025:Morpholines; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; D017480:Receptors, sigma; D051996:Transcription Factor RelA; D000097605:Sigma-1 Receptor; C086055:HTT protein, human; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; C033668:calpastatin