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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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Heat map of miRNAs and predicted gene targets in regions of G93A-SOD1 mouse brain. Regions investigated were brainstem motor nuclei, primary motor cortex, hippocampus and SVZ at week 18. Expression data are means of log2 fold changes (relative to mean values for all brain areas investigated). Blue indicates down-regulation and red indicates up-regulation of miRNAs and predicted gene targets, respectively. Hierarchical clustering analysis identifies two clusters of miRNAs and their predicted targets: one characterizing brainstem motor nuclei and primary motor cortex (areas of neurodegeneration); the other characterizing hippocampus and SVZ (areas of neurogenesis).
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Fig6: Heat map of miRNAs and predicted gene targets in regions of G93A-SOD1 mouse brain. Regions investigated were brainstem motor nuclei, primary motor cortex, hippocampus and SVZ at week 18. Expression data are means of log2 fold changes (relative to mean values for all brain areas investigated). Blue indicates down-regulation and red indicates up-regulation of miRNAs and predicted gene targets, respectively. Hierarchical clustering analysis identifies two clusters of miRNAs and their predicted targets: one characterizing brainstem motor nuclei and primary motor cortex (areas of neurodegeneration); the other characterizing hippocampus and SVZ (areas of neurogenesis).

Mentions: FigureĀ 6 shows expression levels of miRNAs and target mRNAs relative to mean values in all brain areas investigated. Hierarchical clustering analysis identified two clusters of miRNAs and their predicted targets: one characterizing brainstem motor nuclei and primary motor cortex; the other characterizing hippocampus and SVZ.Figure 6


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)

Heat map of miRNAs and predicted gene targets in regions of G93A-SOD1 mouse brain. Regions investigated were brainstem motor nuclei, primary motor cortex, hippocampus and SVZ at week 18. Expression data are means of log2 fold changes (relative to mean values for all brain areas investigated). Blue indicates down-regulation and red indicates up-regulation of miRNAs and predicted gene targets, respectively. Hierarchical clustering analysis identifies two clusters of miRNAs and their predicted targets: one characterizing brainstem motor nuclei and primary motor cortex (areas of neurodegeneration); the other characterizing hippocampus and SVZ (areas of neurogenesis).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig6: Heat map of miRNAs and predicted gene targets in regions of G93A-SOD1 mouse brain. Regions investigated were brainstem motor nuclei, primary motor cortex, hippocampus and SVZ at week 18. Expression data are means of log2 fold changes (relative to mean values for all brain areas investigated). Blue indicates down-regulation and red indicates up-regulation of miRNAs and predicted gene targets, respectively. Hierarchical clustering analysis identifies two clusters of miRNAs and their predicted targets: one characterizing brainstem motor nuclei and primary motor cortex (areas of neurodegeneration); the other characterizing hippocampus and SVZ (areas of neurogenesis).
Mentions: FigureĀ 6 shows expression levels of miRNAs and target mRNAs relative to mean values in all brain areas investigated. Hierarchical clustering analysis identified two clusters of miRNAs and their predicted targets: one characterizing brainstem motor nuclei and primary motor cortex; the other characterizing hippocampus and SVZ.Figure 6

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