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

Marcuzzo S, Bonanno S, Kapetis D, Barzago C, Cavalcante P, D'Alessandro S, Mantegazza R, Bernasconi P - Mol Brain (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Neurology IV - Neuromuscular Diseases and Neuroimmunology Unit, Fondazione Istituto Neurologico "Carlo Besta", Via Celoria 11, Milan, 20133, Italy. stefania.marcuzzo@istituto-besta.it.

ABSTRACT

Background: 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.

Results: 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.

Conclusions: 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.

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Neural and cell cycle-related miRNAs are altered in G93A-SOD1 mouse brain as disease progresses. RT-PCR analysis of brain-specific (A) and cell cycle-related (B) miRNAs in total RNA extracted from whole brain of G93A-SOD1, B6.SJL and Wt-SOD1 mice, at postnatal weeks 8 and 18 (ten mice per group). Each point represents a single brain. Relative expression data are presented as means ± SD. *p < 0.05; **p < 0.01; limma moderated t-test.
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Fig1: Neural and cell cycle-related miRNAs are altered in G93A-SOD1 mouse brain as disease progresses. RT-PCR analysis of brain-specific (A) and cell cycle-related (B) miRNAs in total RNA extracted from whole brain of G93A-SOD1, B6.SJL and Wt-SOD1 mice, at postnatal weeks 8 and 18 (ten mice per group). Each point represents a single brain. Relative expression data are presented as means ± SD. *p < 0.05; **p < 0.01; limma moderated t-test.

Mentions: At 8 weeks expression levels of miR-9, miR-124a, miR-19a and -19b did not differ significantly between whole brains of G93A-SOD1, B6.SJL and Wt-SOD1 mice, except for miR-19a, which was significantly down-regulated in ALS brain (p < 0.05) (Figure 1). At week 18, miR-9, miR-124a, miR-19a and -19b levels were significantly higher in G93A-SOD1 than control brains (p < 0.01 both B6.SJL and Wt-SOD1) (Figure 1). In addition, miR-9 was significantly up-regulated in G93A-SOD1 brain compared to week 8 (p < 0.01).Figure 1


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

Marcuzzo S, Bonanno S, Kapetis D, Barzago C, Cavalcante P, D'Alessandro S, Mantegazza R, Bernasconi P - Mol Brain (2015)

Neural and cell cycle-related miRNAs are altered in G93A-SOD1 mouse brain as disease progresses. RT-PCR analysis of brain-specific (A) and cell cycle-related (B) miRNAs in total RNA extracted from whole brain of G93A-SOD1, B6.SJL and Wt-SOD1 mice, at postnatal weeks 8 and 18 (ten mice per group). Each point represents a single brain. Relative expression data are presented as means ± SD. *p < 0.05; **p < 0.01; limma moderated t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4318136&req=5

Fig1: Neural and cell cycle-related miRNAs are altered in G93A-SOD1 mouse brain as disease progresses. RT-PCR analysis of brain-specific (A) and cell cycle-related (B) miRNAs in total RNA extracted from whole brain of G93A-SOD1, B6.SJL and Wt-SOD1 mice, at postnatal weeks 8 and 18 (ten mice per group). Each point represents a single brain. Relative expression data are presented as means ± SD. *p < 0.05; **p < 0.01; limma moderated t-test.
Mentions: At 8 weeks expression levels of miR-9, miR-124a, miR-19a and -19b did not differ significantly between whole brains of G93A-SOD1, B6.SJL and Wt-SOD1 mice, except for miR-19a, which was significantly down-regulated in ALS brain (p < 0.05) (Figure 1). At week 18, miR-9, miR-124a, miR-19a and -19b levels were significantly higher in G93A-SOD1 than control brains (p < 0.01 both B6.SJL and Wt-SOD1) (Figure 1). In addition, miR-9 was significantly up-regulated in G93A-SOD1 brain compared to week 8 (p < 0.01).Figure 1

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Neurology IV - Neuromuscular Diseases and Neuroimmunology Unit, Fondazione Istituto Neurologico "Carlo Besta", Via Celoria 11, Milan, 20133, Italy. stefania.marcuzzo@istituto-besta.it.

ABSTRACT

Background: 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.

Results: 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.

Conclusions: 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.

Show MeSH
Related in: MedlinePlus