title: SUMO1 promotes Aβ production via the modulation of autophagy.
abstract: Autophagy is one of the main mechanisms in the pathophysiology of neurodegenerative disease. The accumulation of autophagic vacuoles (AVs) in affected neurons is responsible for amyloid-β (Aβ) production. Previously, we reported that SUMO1 (small ubiquitin-like modifier 1) increases Aβ levels. In this study, we explored the mechanisms underlying this. We investigated whether AV formation is necessary for Aβ production by SUMO1. Overexpression of SUMO1 increased autophagic activation, inducing the formation of LC3-II-positive AVs in neuroglioma H4 cells. Consistently, autophagic activation was decreased by the depletion of SUMO1 with small hairpin RNA (shRNA) in H4 cells. The SUMO1-mediated increase in Aβ was reduced by the autophagy inhibitors (3-methyladenine or wortmannin) or genetic inhibitors (siRNA targeting ATG5, ATG7, ATG12, or HIF1A), respectively. Accumulation of SUMO1, ATG12, and LC3 was seen in amyloid precursor protein transgenic mice. Our results suggest that SUMO1 accelerates the accumulation of AVs and promotes Aβ production, which is a key mechanism for understanding the AV-mediated pathophysiology of Alzheimer disease.
authors.affiliation: a Division of Brain Diseases, Center for Biomedical Sciences; Center for Infectious Diseases; Korea National Institute of Health; Osong-eup, Heungdeok-gu , Cheongju-si , Chungcheongbuk-do , Republic of Korea ;
authors.forename: Sun-Jung
authors.initials: SJ
authors.lastname: Cho
authors.forename: Sang-Moon
authors.initials: SM
authors.lastname: Yun
authors.forename: Chulman
authors.initials: C
authors.lastname: Jo
authors.forename: Dae-Hoon
authors.initials: DH
authors.lastname: Lee
authors.forename: Ki Ju
authors.initials: KJ
authors.lastname: Choi
authors.forename: Jae Chun
authors.initials: JC
authors.lastname: Song
authors.forename: Sang Ick
authors.initials: SI
authors.lastname: Park
authors.forename: You-Jin
authors.initials: YJ
authors.lastname: Kim
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Koh
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D025842:SUMO-1 Protein / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D025842:SUMO-1 Protein
keywords: AD, Alzheimer disease; ATG, autophagy-related; ATG12; AV, autophagic vacuole; Alzheimer disease; Aβ, amyloid-β; LC3; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MDC, monodansylcadaverine; SUMO1; SUMO1, small ubiquitin-like modifier 1; TEM, transmission electron microscopy, Tg, transgenic; amyloid; autophagy; shRNA, small hairpin RNA