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

• Published in: Molecular brain Vol. 8; no. 1; p. 5
• Main Authors: Marcuzzo, Stefania, Bonanno, Silvia, Kapetis, Dimos, Barzago, Claudia, Cavalcante, Paola, D’Alessandro, Sara, Mantegazza, Renato, Bernasconi, Pia
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 28.01.2015; BioMed Central
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - pathology; Analysis; Animals; Brain; Brain - metabolism; Care and treatment; Cell Count; Cell Cycle; Cell Differentiation; Comparative analysis; Complications and side effects; Disease Progression; Gene expression; Genes; Hippocampus - pathology; Mice; Mice, Transgenic; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; Nervous system diseases; Neural Stem Cells - metabolism; Neuroglia - metabolism; Neurons; Neurons - metabolism; Neurons - pathology; Organ Specificity - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; Superoxide Dismutase - genetics; Up-Regulation - genetics
• ISSN: 1756-6606; 1756-6606
• DOI: 10.1186/s13041-015-0095-0

Amyotrophic 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. Expression 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. Hierarchical 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.