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2014 MRC성과발표회
Abstract Information
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[
] 기타 (
)
CR6-interacting factor 1 is a key regulator in Aβ-induced
mitochondrial disruption and pathogenesis of Alzheimer’s disease
Sung Min Son and Inhee Mook-Jung
Department of Biochemistry & Biomedical Sciences, Seoul National University College of
Medicine, Seoul, Korea
Mitochondrial dysfunction, often characterized by massive fission and other morphological
abnormalities, is a well-known risk factor for Alzheimer’s disease (AD). One causative mechanism
underlying AD-associated mitochondrial dysfunction is thought to be amyloid beta (Aβ), yet the
pathways between Aβ and mitochondrial dysfunction remain elusive. In this study, we report that
CR6-interacting factor 1 (Crif1), a mitochondrial inner membrane protein, is a key player in Aβ–
induced mitochondrial dysfunction. Specifically, we found that Crif1 levels were down-regulated in
the pathological regions of Tg6799 mice brains, wherein overexpressed Aβ undergoes selfaggregation. Down-regulation of Crif1 was similarly observed in human AD brains as well as in SHSY5Y cells treated with Aβ. In addition, knockdown of Crif1, using RNA interference, induced
mitochondrial dysfunction with phenotypes similar to those observed in Aβ-treated cells. Conversely,
Crif1 overexpression prevented Aβ-induced mitochondrial dysfunction and cell death. Finally, we
show that Aβ-induced down-regulation of Crif1 is mediated by enhanced reactive oxygen species
(ROS) and ROS-dependent sumoylation of the transcription factor Sp1. These results identify the
ROS-Sp1-Crif1 pathway to be a new mechanism underlying Aβ-induced mitochondrial dysfunction
and suggest that ROS-mediated down-regulation of Crif1 is a crucial event in AD pathology. We
propose that Crif1 may serve as a novel therapeutic target in the treatment of AD.
References
[1] Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative
diseases. Nature 2006, 443(7113): 787-795.
[2]
Kim SJ, Kwon MC, Ryu MJ, Chung HK, Tadi S, Kim YK, Kim JM, Lee SH, Park JH,
Kweon GR, Ryu SW, Jo YS, Lee CH, Hatakeyama H, Goto Y, Yim YH, Chung J, Kong
YY, Shong M. CRIF1 is essential for the synthesis and insertion of oxidative
phosphorylation polypeptides in the mammalian mitochondrial membrane. Cell Metab
2012, 16(2): 274-283.
[3] Cha MY, Han SH, Son SM, Hong HS, Choi YJ, Byun J, Mook-Jung I. Mitochondriaspecific accumulation of amyloid beta induces mitochondrial dysfunction leading to
apoptotic cell death. PLoS One 2012, 7(4): e34929.
Keywords
: Crif1, Mitochondria, ROS, Sp1, Aβ, Alzheimer’s disease
2014
MRC 성과발표회
Name : Sung Min Son
Affiliation : Department of Biochemistry & Biomedical Sciences,
Seoul National University College of Medicine
Position : Postdoctoral Fellow
E-mail : [email protected]
Field of Expertise : Protein degradation, Cell death, Autophagy
Education
2008.3 – 2013.2 Ph. D. Biomedical Science, Seoul National University College of Medicine
2006.3 – 2008.2 M. S. Interdisciplinary program in Brain Science, Seoul National University
1999.3 – 2006.2 B. S. Genetic engineering, Sungkyunkwan University
Professional Experience
2014.6 – Present
Senior Research Scientist
Institute for Neurosciences, Seoul National University College of Medicine
2013.2 – 2014.5 Postdoctoral Research Fellow
Department of Biomedical Sciences, Seoul National University College of Medicine
Selected Publications :
1. *Byun J, *Son SM, Cha MY, Shong M, Hwang YJ, Kim Y, Ryu H, Moon M, Kim KS, MookJung I. CR6-interacting factor 1 is a key regulator in Aβ-induced mitochondrial disruption and
pathogenesis of Alzheimer’s disease. Cell Death and Differentiation. 2014. (In press) (*Cofirst author)
2. Son SM, Byun J, Roh S-E, Kim SJ, Mook-Jung I. Reduced IRE1α mediates apoptotic cell
death by disrupting calcium homeostasis via the InsP3 receptor. Cell Death and Disease.
2014 Apr 17;5:e1188. doi: 10.1038/cddis.2014.129.
3. Son SM, Song H, Byun J, Park KS, Jang HC, Park YJ, Mook-Jung I. Accumulation of
autophagosomes contributes to enhanced amyloidogenic APP processing under insulinresistant conditions. Autophagy. 2012 Dec;8(12):1842-4.
4. Son SM, Song H, Byun J, Park KS, Jang HC, Park YJ, Mook-Jung I. Altered APP
Processing in Insulin-Resistant Conditions Is Mediated by Autophagosome Accumulation via
the Inhibition of Mammalian Target of Rapamycin Pathway. Diabetes. 2012 Dec;61(12):312638.
5. Son SM, Jung ES, Shin HJ, Byun J, Mook-Jung I. Aβ-induced autophagosome formation
is mediated by RAGE-CaMKKβ-AMPK signaling pathway. Neurobiology of Aging. 2012
May;33(5):1006.e11-23. Epub 2011 Nov 1.