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Study on the role of SUMO1 on β-amyloid accumulation in alzheimer's disease 원문보기

  • 저자

    윤상문

  • 학위수여기관

    Graduate School, Korea University

  • 학위구분

    국내박사

  • 학과

    生命工學科

  • 지도교수

    고영호,최의주

  • 발행년도

    2014

  • 총페이지

    xiv, 109 p.

  • 키워드

    Alzheimer's disease BACE1 SUMO1 APP β-amyloid;

  • 언어

    eng

  • 원문 URL

    http://www.riss.kr/link?id=T13541923&outLink=K  

  • 초록

    Accumulation of disease-related proteins is characteristic events observed in the pathogenesis of neurodegenerative diseases. Small ubiquitin-like modifier (SUMO) protein has been shown to be implicated in aggregation of several neurodegenerative-disease-related proteins, such as α-synuclein and Huntingtin. However, the roles of SUMO in Alzheimer's disease (AD) are largely unclear. In this study, the elevation of small ubiquitin-like modifier 1 (SUMO1) levels are observed in AD model mice, which had abundant amyloid plaque. Interestingly, SUMO1 immunoreactivity was enhanced around amyloid plaque in the AD model mice. Moreover, exogenous treatment of Aβ peptide led to SUMO1 increase in primary cultured neurons and H4 neuroglioma cells. These results suggest that elevation of β-amyloid (Aβ) in AD promotes SUMO1 levels. SUMO is supposed to be implicated in the pathogenesis of several neurodegenerative disease. Therefore, I investigated the effect on Aβ production by SUMO. Overexpression Experiments showed that the SUMO led to a substantial increase in Aβ production. On the other hand, Aβ secretion by only SUMO1 depletion decreased using siRNA and shRNA, suggesting that SUMO1 could have the role on Aβ accumulation. The present results are supposed to be a positive feedback regulation between Aβ and SUMO1. Next I inquired further the role of SUMO1 on amyloid precursor protein (APP) processing. β-secretase (BACE1) protein, which initiates generation of Aβ, was found to be regulated by SUMO1. But Nicastrin, one of the γ-secretase complex could not be observed to mediate the effect of SUMO on Aβ production. BACE1 modulation by SUMO was not caused by transcriptional or translational regulation. BACE1 protein partially co-stained and interacted with SUMO1 protein, which depended on the dileucine motif of BACE1. This was proved by the co-immunoprecipitation, gain- or loss- of- functional SUMO experiments. The present results suggested that dileucine motif of BACE1 is required for the interaction with SUMO1 and BACE1, as well as BACE1 accumulation by SUMO1. Interestingly, it was observed that Aβ gave rise to BACE1 elevation, as well as SUMO1 induction. However, alteration of Nicastrin, one of γ-secretase complex, was not seen by Aβ peptide. BACE1 levels were increased in response to Aβ or apoptosis, but not in cells lacking SUMO1, demonstrating that BACE1 accumulation by Aβ or apoptosis is mediated via SUMO1. Furthermore, the C-terminus fragments of BACE1 containing dileucine motif reduced Aβ generation by SUMO1 overexpression. Because BACE1wt and fragments including BACE1 dileucine motif can comple for interation with SUMO1, this result suggests the possibility of SUMO1 as target for Aβ reduction. Taken together, the present data demonstrated that altering SUMO1 affects BACE1 protein levels, and consequently results in altered APP processing and Aβ accumulation. An elevated Aβ in turn leads to increased SUMO1. These positive feedback regulation between SUMO1, BACE1 and Aβ accumulation suggest understanding pathogenetic role of SUMO1 in Alzheimer's disease. In summary, this study implicates SUMO1 is a novel and potent regulator of BACE1 and Aβ accumulation, a potential therapeutic target for Alzheimer's disease.


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