SUMO1 modulates Aβ generation via BACE1 accumulation

Sang Moon Yun, Sun Jung Cho, Jae Chun Song, Sung Yeon Song, Sangmee Ahn Jo, Chulman Jo, Keejung Yoon, Rudolph E. Tanzi, Eui Ju Choi, Young Ho Koh

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36 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)650-662
Number of pages13
JournalNeurobiology of Aging
Volume34
Issue number3
DOIs
Publication statusPublished - 2013 Mar 1

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Keywords

  • Alzheimer's disease
  • Amyloid peptide
  • BACE1
  • SUMO1

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Ageing
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Yun, S. M., Cho, S. J., Song, J. C., Song, S. Y., Jo, S. A., Jo, C., Yoon, K., Tanzi, R. E., Choi, E. J., & Koh, Y. H. (2013). SUMO1 modulates Aβ generation via BACE1 accumulation. Neurobiology of Aging, 34(3), 650-662. https://doi.org/10.1016/j.neurobiolaging.2012.08.005