title: Downregulation of Homer1b/c in SOD1 G93A Models of ALS: A Novel Mechanism of Neuroprotective Effect of Lithium and Valproic Acid.
abstract: BACKGROUND
  Mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been linked to amyotrophic lateral sclerosis (ALS). However, the molecular mechanisms have not been elucidated yet. Homer family protein Homer1b/c is expressed widely in the central nervous system and plays important roles in neurological diseases. In this study, we explored whether Homer1b/c was involved in SOD1 mutation-linked ALS.
  
  
  RESULTS
  In vitro studies showed that the SOD1 G93A mutation induced an increase of Homer1b/c expression at both the mRNA and protein levels in NSC34 cells. Knockdown of Homer1b/c expression using its short interfering RNA (siRNA) (si-Homer1) protected SOD1 G93A NSC34 cells from apoptosis. The expressions of Homer1b/c and apoptosis-related protein Bax were also suppressed, while Bcl-2 was increased by lithium and valproic acid (VPA) in SOD1 G93A NSC34 cells. In vivo, both the mRNA and protein levels of Homer1b/c were increased significantly in the lumbar spinal cord in SOD1 G93A transgenic mice compared with wild type (WT) mice. Moreover, lithium and VPA treatment suppressed the expression of Homer1b/c in SOD1 G93A mice.
  
  
  CONCLUSIONS
  The suppression of SOD1 G93A mutation-induced Homer1b/c upregulation protected ALS against neuronal apoptosis, which is a novel mechanism of the neuroprotective effect of lithium and VPA. This study provides new insights into pathogenesis and treatment of ALS.
authors.affiliation: Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China. jianghz@hrbmu.edu.cn.
authors.forename: Hai-Zhi
authors.initials: HZ
authors.lastname: Jiang
authors.affiliation: Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China. WangS319@hotmail.com.
authors.forename: Shu-Yu
authors.initials: SY
authors.lastname: Wang
authors.affiliation: Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China. YinXiang15@hotmail.com.
authors.forename: Xiang
authors.initials: X
authors.lastname: Yin
authors.affiliation: Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China. jianghongquan321@hotmail.com.
authors.forename: Hong-Quan
authors.initials: HQ
authors.lastname: Jiang
authors.affiliation: Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China. wangxudonghlj@hotmail.com.
authors.forename: Xu-Dong
authors.initials: XD
authors.lastname: Wang
authors.affiliation: Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China. hebgdwangjing@163.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China. libu979@126.com.
authors.forename: Tian-Hang
authors.initials: TH
authors.lastname: Wang
authors.affiliation: Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China. qiswallow21@sohu.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China. yangyueqing714@sina.com.
authors.forename: Yue-Qing
authors.initials: YQ
authors.lastname: Yang
authors.affiliation: Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China. try101_80@163.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China. hoat77@sina.com.
authors.forename: Chun-Ting
authors.initials: CT
authors.lastname: Zhang
authors.affiliation: Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China. fenghonglin_186@sina.com.
authors.forename: Hong-Lin
authors.initials: HL
authors.lastname: Feng
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D020022:Genetic Predisposition to Disease; D000072233:Homer Scaffolding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008094:Lithium / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics*; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: D000072233:Homer Scaffolding Proteins; C000606623:Homer1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D014635:Valproic Acid; D008094:Lithium; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase
keywords: Homer1b/c; SOD1 G93A; amyotrophic lateral sclerosis; lithium; valproic acid (VPA)