title: SUMO1 modulates Aβ generation via BACE1 accumulation.
abstract: Accumulation of disease-related proteins is a characteristic event observed in the pathogenesis of neurodegenerative diseases. β-secretase (BACE)-1, which initiates generation of β-amyloid (Aβ), is increased in the Alzheimer's diseased brain. However, the mechanisms of BACE1 accumulation in Alzheimer's disease are largely unknown. In this report, we found that small ubiquitin-like modifier (SUMO)-1 interacts with the dileucine motif of BACE1 and regulates the level of BACE1 protein. This was proved by the coimmunoprecipitation, and gain or loss of function experiments. Altering 3 SUMO isoforms affects BACE1 protein levels, and consequently results in altered amyloid precursor protein processing and Aβ generation. BACE1 levels were increased in response to Aβ or apoptosis, but not in cells lacking SUMO1. Aβ increased SUMO1 protein levels in rat cortical neurons. Moreover, SUMO1 immunoreactivity was increased in the amyloid precursor protein transgenic mice. Furthermore, the C-terminus fragments of BACE1 containing dileucine motif reduced Aβ generation by SUMO1 overexpression. Our study indicates SUMO1 is not only a novel and potent regulator of BACE1 accumulation and Aβ generation but also a potential therapeutic target for Alzheimer's disease.
authors.affiliation: Division of Brain Diseases, Center for Biomedical Sciences, Korea National Institute of Health, Chungcheongbuk-do, Republic of Korea.
authors.forename: Sang-Moon
authors.initials: SM
authors.lastname: Yun
authors.forename: Sun-Jung
authors.initials: SJ
authors.lastname: Cho
authors.forename: Jae Chun
authors.initials: JC
authors.lastname: Song
authors.forename: Sung Yeon
authors.initials: SY
authors.lastname: Song
authors.forename: Sangmee Ahn
authors.initials: SA
authors.lastname: Jo
authors.forename: Chulman
authors.initials: C
authors.lastname: Jo
authors.forename: Keejung
authors.initials: K
authors.lastname: Yoon
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.forename: Eui-Ju
authors.initials: EJ
authors.lastname: Choi
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Koh
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D020816:Amino Acid Motifs; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025842:SUMO-1 Protein / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D025842:SUMO-1 Protein; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse