Up-regulation of neural and cell cycle-related microRNAs in brain of amyotrophic lateral sclerosis mice at late disease stage

Abstract

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective motor neuron degeneration in motor cortex, brainstem and spinal cord. microRNAs (miRNAs) are small non-coding RNAs that bind complementary target sequences and modulate gene expression; they are key molecules for establishing a neuronal phenotype, and in neurodegeneration. Here we investigated neural miR-9, miR-124a, miR-125b, miR-219, miR-134, and cell cycle-related miR-19a and -19b, in G93A-SOD1 mouse brain in pre-symptomatic and late stage disease.ResultsExpression of miR-9, miR-124a, miR-19a and -19b was significantly increased in G93A-SOD1 whole brain at late stage disease compared to B6.SJL and Wt-SOD1 control brains. These miRNAs were then analyzed in manually dissected SVZ, hippocampus, primary motor cortex and brainstem motor nuclei in 18-week-old ALS mice compared to same age controls. In SVZ and hippocampus miR-124a was up-regulated, miR-219 was down-regulated, and numbers of neural stem progenitor cells (NSPCs) were significantly increased. In G93A-SOD1 brainstem motor nuclei and primary motor cortex, miR-9 and miR-124a were significantly up-regulated, miR-125b expression was also increased. miR-19a and -19b were up-regulated in primary motor cortex and hippocampus, respectively. Expression analysis of predicted miRNA targets identified miRNA/target gene pairs differentially expressed in G93A-SOD1 brain regions compared to controls.ConclusionsHierarchical clustering analysis, identifying two clusters of miRNA/target genes, one characterizing brainstem motor nuclei and primary motor cortex, the other hippocampus and SVZ, suggests that altered expression of neural and cell cycle-related miRNAs in these brain regions might contribute to ALS pathogenesis in G93A-SOD1 mice. Re-establishing their expression to normal levels could be a new therapeutic approach to ALS.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0095-0) contains supplementary material, which is available to authorized users.

ALS and FTD: an epigenetic perspective

“…Moreover, the authors found correlative levels of miR-124 and AMPAR in induced pluripotent stem cell-derived neurons from subjects with behavioral variant FTD, supporting investigation of targeting this miRNA for FTD therapy. Several more studies have identified additional alternatively expressed miRNAs in ALS and FTD that could be developed as drug targets or as circulatory biomarkers for ALS [37,69,87,108,133,173,194]. For example, miR-206 was consistently altered during the course disease in SOD1 -Gly93Ala mice and increased in the circulation of a small cohort of ALS patients [173].…”

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

“…There is growing evidence of the involvement of miRNA deregulation in ALS pathogenesis [207][208][209][210][211]. Changes in miRNA expression have been found in patients and the SOD1 G93A mouse [176,212,213] reflecting a dysfunction of the expressed RNA binding proteins involved in ALS.…”

A role for miR-19 in the migration of adult-born neurons and schizophrenia

“…The different expression levels and functional contributions of each miRNA family have been shown in the developmental brain; 14,15,22-24 however, it has been studied less extensively in the adult brain. Abnormal expression of each miRNA family has been reported in adult brains of human patients with Alzheimer disease 25 or schizophrenia (SZ) 26,27 as well as in a mouse model for amyotrophic lateral sclerosis, 28 implying different biological impacts of each miRNA family in the adult brain.…”