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2014 MRC성과발표회 Abstract Information [ ] 심포지엄 구연 발표 [ O ] 기초의과학 학문후속세대 발표 Category (연제와 관련있는 분야에 모두 표시해 주십시오) [ O ] Aging and age-related diseases [ ] Alternative medicine [ ] Anatomical methodology [ ] Anticancer strategies [ ] Bioengineering and technology [ ] Biology of development [ ] Biomarkers for personalized medicine [ ] Biomedical informatics [ ] Cancer biology (oncological sciences) [ O ] Cellular injuries, death, apoptosis, autophagy [ ] Clinical pharmacology [ ] Craniofacial diseases [ ] Developmental Biology and Cell Differentiation [ ] DNA Replication, DNA Damage and Cell Cycle [ ] Drug: mechanism of action & toxicity [ ] Endocrinology and metabolism [ ] Enzyme: mechanism of action and regulation [ ] Gene expression [ ] Gene-, Cell-, & Immunotherapy [ ] Genetics and Epigenetics [ ] Gross anatomy [ ] Herb medicine and phytochemicals [ ] Histology of organs [ ] Immunology [ ] Inflammation and tissue injury [ ] Infectious diseases: bacteriology, virology and mycology [ ] Ion, ion channel & excitability [ ] Membrane transport & secretion [ ] Metabolic diseases [ ] Molecular and Cellular Aspects of Behaviour [ O ] Neuroscience and Neurobiology [ ] Novel Targets for Drug Development and Screening Candidates [ ] Omics and Systems Biology [ ] Orofacial Diseases [ ] Protein Biochemistry: Structure, Function, and Modification [ ] Parasitology and parasitic diseases [ ] Pharmacogenetics [ ] Preventive medicine [ ] RNA Biology and Application [ ] Signal transduction [ ] Stem cells and regeneration [ ] Therapeutic approaches of Korean Medicine [ ] Vascular Biology and Medicine [ ] 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.