title: Downregulation of proteins involved in the endoplasmic reticulum stress response and Nrf2-ARE signaling in lymphoblastoid cells of spinocerebellar ataxia type 17.
abstract: Spinocerebellar ataxia type 17 (SCA17) is caused by CAG repeat expansion in the TATA-box binding protein gene. Studies of several polyglutamine (polyQ) expansion diseases have suggested that the expanded polyQ proteins misfold and induce oxidative stress to contribute to cell death. Substantial deficits in peripheral tissues including lymphocytes have been shown and these peripheral abnormalities could also be found in neurons possessing polyQ disease proteins. In this study, we used a lymphoblastoid cell model to investigate the functional implication of SCA17 expanded alleles and assess the potential therapeutic strategies that may ameliorate the effects of expanded polyQ. Proteomics studies of patient/control pairs including two-dimensional (2-D) gel electrophoresis, mass spectrometry and immunoblotting were conducted. A total of 8 proteins with reduced expression changes greater than 1.3-fold were identified, including previously reported HSPA5 and HSPA8. Among 6 proteins further semi-quantified by immunoblotting and real-time PCR, the reduced expression of HYOU1, PDIA3, P4HB, NQO1 and HMOX1 was confirmed. Treatment with resveratrol and genipin up-regulated NQO1 and HMOX1 expression and reduced oxidative stress in patients' lymphoblastoid cells. The results illustrate downregulation of proteins involved in the endoplasmic reticulum stress response (HYOU1, HSPA5, PDIA3, and P4HB) and Nrf2-ARE signaling (NQO1 and HMOX1) in SCA17 lymphoblastoid cells. Compounds increasing anti-oxidative activity such as resveratrol and genipin may serve as a potential therapeutic strategy for SCA17.
authors.affiliation: Department of Life Science, National Taiwan Normal University, 88 Ting-Chou Road, Section 4, Taipei, 11677, Taiwan.
authors.forename: Li-Ching
authors.initials: LC
authors.lastname: Lee
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Weng
authors.forename: Yih-Ru
authors.initials: YR
authors.lastname: Wu
authors.forename: Bing-Wen
authors.initials: BW
authors.lastname: Soong
authors.forename: Yung-Che
authors.initials: YC
authors.lastname: Tseng
authors.forename: Chiung-Mei
authors.initials: CM
authors.lastname: Chen
authors.forename: Guey-Jen
authors.initials: GJ
authors.lastname: Lee-Chen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015180:Electrophoresis, Gel, Two-Dimensional; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010455:Peptides / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000473:pathology*; D035181:TATA-Box Binding Protein / Q000235:genetics; D055815:Young Adult
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010455:Peptides; D035181:TATA-Box Binding Protein; C509817:TBP protein, human; C097188:polyglutamine