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. 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.

Valproic Acid and Epilepsy: From Molecular Mechanisms to Clinical Evidences

“…VPA neuroprotective properties are not exclusive to Parkinson's disease, but have been reported in several other neurodegenerative conditions and models, from Huntington's disease to amyloid beta-peptide induced neurotoxicity and amyotrophic lateral sclerosis [126,127]. Regarding the latter, in an ALS animal model, VPA was able to reduce the expression of Homer1b/c, modulating apoptosis and neuronal loss and promoting neuronal protection and survival [128]. Further studies are on the verge of assessing the clinical benefit of VPA use as a neuroprotective agent in humans.…”

In a search for efficient treatment for amyotrophic lateral sclerosis: Old drugs for new approaches

“…[50][51][52][53][54][55] Further studies revealed that only patients homozygous for C allele of UNC13A locus, which is known to be genetically linked to ALS and FTLD, [56][57][58] response to lithium therapy. 59 Cotreatment with lithium and valproic acid has also been tested in animal models 40,60 and used in a small size clinical trial in patients with sALS that revealed increased survival and signs of neuroprotection although doses used were too high and caused side-effects that forced termination of the trial. 61 Results of another clinical trial of lithium and valproic acid cotreatment (NCT03204500) are not yet published.…”

“…In particular, lithium, an inhibitor of glycogen synthase kinase 3 (GSK‐3), and valproic acid, an inhibitor of histone deacetylases (HDACs), have been tested in animal models and ALS clinical trials. The rationale for testing these drugs was their neuroprotective potential, that has been linked to their ability to interfere with many pathways and processes involved in neuronal death, including excitotoxicity, 39 expression of glutamatergic postsynaptic density proteins of Homer family, 40,41 aberrant Notch signaling, 42 apoptosis, 43 endoplasmic reticulum stress (ERS), and autophagy 39,44 . Moreover, a synergistic effect of these two drugs has been demonstrated 45,46 .…”

Differential Expression of Multiple Disease-Related Protein Groups Induced by Valproic Acid in Human SH-SY5Y Neuroblastoma Cells

“…For example, microarray analysis of rat brain genes identified a variety of protein pathways modulated by VPA, including synaptic transmission, ion channels and transport, G-protein signaling, lipid, glucose, and amino acid metabolism, transcriptional and translational regulation, the phosphoinositol cycle, protein kinases and phosphatases, and apoptosis [ 9 ]. Du et al reported in their study that the downregulation of transient receptor potential channel 1 (TRPC1) gene expression and function in neurons may be involved in the mood-stabilizing action of VPA [ 10 ], while Jiang et al suggested that the downregulation of Homer1b/c is a potential mechanism for the neuroprotective effects of VPA and lithium [ 11 ].…”