title: Mutant presenilin2 promotes apoptosis through the p53/miR-34a axis in neuronal cells.
abstract: Neurodegenerative disorders have attracted attention in last decades due to their high incidence in the world. The p53/miR-34a axis triggers apoptosis and suppresses viability in multiple types of cells, but little is known about its role in neurodegenerative diseases. In this study, we showed that presenilin (PS)-2, a major gene associated with familial Alzheimer's disease (AD) could trigger the apoptosis through the p53/miR-34a axis in PC12 cells. First we found that PC12 cell viability was downregulated by PS-2 and mutant PS-2 overexpression, especially by mutant PS-2 overexpression. Then, we established a mutant PS-2-overexpressing PC12 cell line and confirmed that mutant PS-2 induced not only p53 but also miR-34a expression. The transfection of miR-34a inhibitor reversed PS-2-induced effects on cellular viability and apoptosis. Mutant PS-2 overexpression promoted caspase-3 expression, reduced Sirt1 and Bcl-2 expression, all of which were miR-34a downstream genes related with cell apoptosis. Moreover, mutant PS-2 also activated the p53/miR-34a axis and induced apoptosis in AD transgenic mice brain. These results implied that mutant PS-2 might promote the apoptosis of neuronal cells through triggering the p53/miR-34a axis. Altogether our results provide a novel insight into neurodegenerative disease and deepen our understandings of AD pathogenic processes.
authors.affiliation: Department of Neurology, The Third Xiangya Hospital of Central South University, No. 138, Tong Zipo Rd, Yuelu District, Changsha, China.
authors.forename: Liu-Hong
authors.initials: LH
authors.lastname: Li
authors.affiliation: Department of Geratology, The Third Xiangya Hospital of Central South University, No. 138, Tong zipo Rd, Yuelu District, Changsha, China.
authors.forename: Qiu-Yun
authors.initials: QY
authors.lastname: Tu
authors.affiliation: Department of Human Anatomy, College of Basic Medicine, Central South University, No. 172, Tong zipo Rd, Yuelu District, Changsha, China.
authors.forename: Xiao-Hua
authors.initials: XH
authors.lastname: Deng
authors.affiliation: Department of Neurology, The Xiangya Hospital of Central South University, No. 87, Xiangya Road, Kaifu District, Changsha, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Xia
authors.affiliation: Department of Neurology, The Third Xiangya Hospital of Central South University, No. 138, Tong Zipo Rd, Yuelu District, Changsha, China.
authors.forename: De-Ren
authors.initials: DR
authors.lastname: Hou
authors.affiliation: Department of Neurology, The Third Xiangya Hospital of Central South University, No. 138, Tong Zipo Rd, Yuelu District, Changsha, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Guo
authors.affiliation: Department of Neurology, The Third Xiangya Hospital of Central South University, No. 138, Tong Zipo Rd, Yuelu District, Changsha, China. Electronic address: lixiaoz2002@aliyun.com.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Zi
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D016158:Genes, p53; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000235:genetics; D016716:PC12 Cells; D053766:Presenilin-2 / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D053766:Presenilin-2; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D053148:Caspase 3; D056564:Sirtuin 1
keywords: Alzheimer’s disease; Apoptosis; Bcl-2; Presenilin 2; Sirt1; The p53/miR-34a axis