SUMO1 modulates A beta generation via BACE1 accumulation

Abstract

Accumulation of disease-related proteins is a characteristic event observed in the pathogenesis of neurodegenerative diseases. beta-secretase (BACE)-1, which initiates generation of beta-amyloid (A beta), 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 A beta generation. BACE1 levels were increased in response to A beta or apoptosis, but not in cells lacking SUMO1. A beta 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 A beta generation by SUMO1 overexpression. Our study indicates SUMO1 is not only a novel and potent regulator of BACE1 accumulation and A beta generation but also a potential therapeutic target for Alzheimer's disease. (c) 2013 Elsevier Inc. All rights reserved.