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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
Author to whom correspondence should be addressed.
Academic Editors: Katalin Prokai-Tatrai and Maurizio Battino
Int. J. Mol. Sci. 2016, 17(12), 2129;
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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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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