Downregulation of Homer1b/c in SOD1 G93A Models of ALS: A Novel Mechanism of Neuroprotective Effect of Lithium and Valproic Acid

• Published in: International journal of molecular sciences Vol. 17; no. 12; p. 2129
• Main Authors: Jiang, Hai-Zhi, Wang, Shu-Yu, Yin, Xiang, Jiang, Hong-Quan, Wang, Xu-Dong, Wang, Jing, Wang, Tian-Hang, Qi, Yan, Yang, Yue-Qing, Wang, Ying, Zhang, Chun-Ting, Feng, Hong-Lin
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 17.12.2016; MDPI
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - pathology; Amyotrophic Lateral Sclerosis - therapy; Animals; Apoptosis - genetics; Cell Line; Genetic Predisposition to Disease; Homer Scaffolding Proteins - antagonists & inhibitors; Homer Scaffolding Proteins - biosynthesis; Homer Scaffolding Proteins - genetics; Humans; Lithium; Lithium - therapeutic use; Mice; Mice, Transgenic; Mutation; Proto-Oncogene Proteins c-bcl-2 - metabolism; RNA Interference; RNA, Small Interfering - genetics; Superoxide Dismutase - genetics; Valproic Acid - therapeutic use; Homer1b/c; SOD1 G93A; lithium; valproic acid (VPA); amyotrophic lateral sclerosis
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms17122129

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. Conclusion: 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.