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Int. J. Mol. Sci. 2016, 17(12), 2129; doi:10.3390/ijms17122129

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

Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
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Academic Editors: Katalin Prokai-Tatrai and Maurizio Battino
Received: 25 July 2016 / Revised: 5 December 2016 / Accepted: 9 December 2016 / Published: 17 December 2016
(This article belongs to the Special Issue Neuroprotective Strategies 2016)
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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. 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. View Full-Text
Keywords: Homer1b/c; amyotrophic lateral sclerosis; SOD1 G93A; lithium; valproic acid (VPA) Homer1b/c; amyotrophic lateral sclerosis; SOD1 G93A; lithium; valproic acid (VPA)
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Jiang, H.-Z.; Wang, S.-Y.; Yin, X.; Jiang, H.-Q.; Wang, X.-D.; Wang, J.; Wang, T.-H.; Qi, Y.; Yang, Y.-Q.; Wang, Y.; Zhang, C.-T.; Feng, H.-L. Downregulation of Homer1b/c in SOD1 G93A Models of ALS: A Novel Mechanism of Neuroprotective Effect of Lithium and Valproic Acid. Int. J. Mol. Sci. 2016, 17, 2129.

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