title: Role of high mobility group box 1 (HMGB1) in SCA17 pathogenesis.
abstract: Spinocerebellar ataxia type 17 (SCA17) involves the expression of a polyglutamine (polyQ) expanded TATA-binding protein (TBP), a general transcription initiation factor. TBP interacts with other protein factors, including high mobility group box 1 (HMGB1), to regulate gene expression. Previously, our proteomic analysis of soluble proteins prepared from mutant TBP (TBP/Q61) expressing cells revealed a reduced concentration of HMGB1. Here, we show that HMGB1 can be incorporated into mutant TBP aggregates, which leads to reduced soluble HMGB1 levels in TBP/Q(61∼79) expressing cells. HMGB1 overexpression reduced mutant TBP aggregation. HMGB1 cDNA and siRNA co-transfection, as well as an HSPA5 immunoblot and luciferase reporter assay demonstrated the important role of HMGB1 in the regulation of HSPA5 transcription. In starvation-stressed TBP/Q36 and TBP/Q79 cells, increased reactive oxygen species generation accelerated the cytoplasmic translocation of HMGB1, which accompanied autophagy activation. However, TBP/Q79 cells displayed a decrease in autophagy activation as a result of the reduction in the cytoplasmic HMGB1 level. In neuronal SH-SY5Y cells with induced TBP/Q(61∼79) expression, HMGB1 expression was reduced and accompanied by a significant reduction in the total outgrowth and branches in the TBP/Q(61∼79) expressing cells compared with the non-induced cells. The decreased soluble HMGB1 and impaired starvation-induced autophagy in cells suggest that HMGB1 may be a critical modulator of polyQ disease pathology and may represent a target for drug development.
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Li-Ching
authors.initials: LC
authors.lastname: Lee
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang-Gung University College of Medicine, Taipei, Taiwan.
authors.forename: Chiung-Mei
authors.initials: CM
authors.lastname: Chen
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Pin-Rong
authors.initials: PR
authors.lastname: Wang
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Ming-Tsan
authors.initials: MT
authors.lastname: Su
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Guey-Jen
authors.initials: GJ
authors.lastname: Lee-Chen
authors.affiliation: Science Education Center, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Chun-Yen
authors.initials: CY
authors.lastname: Chang
mesh_terms: D001343:Autophagy / Q000235:genetics; D003593:Cytoplasm / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018384:Oxidative Stress; D020754:Spinocerebellar Ataxias / Q000235:genetics*; D035181:TATA-Box Binding Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D024243:HMGB1 Protein; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D035181:TATA-Box Binding Protein