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MicroRNAs in the pathophysiology and treatment of status epilepticus.

Henshall DC - Front Mol Neurosci (2013)

Bottom Line: Emerging work in animal models has found that SE produces select changes to miRNAs within the brain.Similar changes in over 20 miRNAs have been found in the hippocampus in two or more studies, suggesting conserved miRNA responses after SE.Intracerebral delivery of chemically modified antisense oligonucleotides (antagomirs) has been shown to have potent, specific and long-lasting effects on brain levels of miRNAs.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland Dublin, Ireland.

ABSTRACT
MicroRNA (miRNA) are an important class of non-coding RNA which function as post-transcriptional regulators of gene expression in cells, repressing and fine-tuning protein output. Prolonged seizures (status epilepticus, SE) can cause damage to brain regions such as the hippocampus and result in cognitive deficits and the pathogenesis of epilepsy. Emerging work in animal models has found that SE produces select changes to miRNAs within the brain. Similar changes in over 20 miRNAs have been found in the hippocampus in two or more studies, suggesting conserved miRNA responses after SE. The miRNA changes that accompany SE are predicted to impact levels of multiple proteins involved in neuronal morphology and function, gliosis, neuroinflammation, and cell death. miRNA expression also displays select changes in the blood after SE, supporting blood genomic profiling as potential molecular biomarkers of seizure-damage or epileptogenesis. Intracerebral delivery of chemically modified antisense oligonucleotides (antagomirs) has been shown to have potent, specific and long-lasting effects on brain levels of miRNAs. Targeting miR-34a, miR-132 and miR-184 has been reported to alter seizure-induced neuronal death, whereas targeting miR-134 was neuroprotective, reduced seizure severity during status epilepticus and reduced the later emergence of recurrent spontaneous seizures. These studies support roles for miRNAs in the pathophysiology of status epilepticus and miRNAs may represent novel therapeutic targets to reduce brain injury and epileptogenesis.

No MeSH data available.


Related in: MedlinePlus

(A) Cartoon showing the site and mechanism of miRNA targeting to mRNA. Figure highlights the seven nucleotide “seed” region critical for miRNA binding to the mRNA target. Additional binding also determines specificity and potency. Alignment is facilitated by initial miRNA loading into the RISC which contains Ago2 and GW182 proteins. Binding typically occurs within the 3′UTR. The result is either degradation of the mRNA target or inhibition of translation. (B) Cartoon depicting scheme whereby miRNAs influence gene expression after SE. Status epilepticus results in transcriptional up-regulation of 100s of genes. miRNAs lie downstream of this and exert influence over protein production and as a result, influence post-injury outcomes such as repair, cell death and reorganization. Such miRNAs represent potential treatment targets to interrupt pathogenesis of damage and long-term consequences (e.g., hyperexcitability).
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Figure 1: (A) Cartoon showing the site and mechanism of miRNA targeting to mRNA. Figure highlights the seven nucleotide “seed” region critical for miRNA binding to the mRNA target. Additional binding also determines specificity and potency. Alignment is facilitated by initial miRNA loading into the RISC which contains Ago2 and GW182 proteins. Binding typically occurs within the 3′UTR. The result is either degradation of the mRNA target or inhibition of translation. (B) Cartoon depicting scheme whereby miRNAs influence gene expression after SE. Status epilepticus results in transcriptional up-regulation of 100s of genes. miRNAs lie downstream of this and exert influence over protein production and as a result, influence post-injury outcomes such as repair, cell death and reorganization. Such miRNAs represent potential treatment targets to interrupt pathogenesis of damage and long-term consequences (e.g., hyperexcitability).

Mentions: MiRNAs control protein output by binding to specific, complementary sequences in target mRNAs of protein-coding genes. MiRNA binding sites are most often found in the 3′untranslated region (UTR) but have also been identified at the 5′end and within the open reading frame (ORF; Bartel, 2009). In mammals, miRNAs usually do not have complete complementarity to the mRNA sequence and therefore do not trigger direct cleavage of the mRNA as occurs with the RNA interference pathway activated by short interfering RNAs (Krol et al., 2010). However, mRNA levels of targets are often reduced by miRNA targeting (Lim et al., 2005; Guo et al., 2010). Targeting involves a 7–8 nucleotide “seed” region within the 5′ end of the miRNA binding to the mRNA via Watson–Crick base-pairing, followed by a variable number of further binding sites (Bartel, 2009; Figure 1A). The molecular machinery driving this process is the RISC which is a multi-protein complex, comprising members of the argonaute family as well as GW182 proteins (Fabian et al., 2010). Ago2 is critical in loading the miRNA and bringing it together with the mRNA target. The effect of miRNA targeting of a mRNA can be inhibition of translation or deadenylation and subsequent degradation, or both (Fabian et al., 2010). RISCs containing miRNA and their targets may also be sequestered in processing (P) bodies, including at synapses, which is reversible, enabling later release of the mRNA for translation (Cougot et al., 2008; Saugstad, 2010).


MicroRNAs in the pathophysiology and treatment of status epilepticus.

Henshall DC - Front Mol Neurosci (2013)

(A) Cartoon showing the site and mechanism of miRNA targeting to mRNA. Figure highlights the seven nucleotide “seed” region critical for miRNA binding to the mRNA target. Additional binding also determines specificity and potency. Alignment is facilitated by initial miRNA loading into the RISC which contains Ago2 and GW182 proteins. Binding typically occurs within the 3′UTR. The result is either degradation of the mRNA target or inhibition of translation. (B) Cartoon depicting scheme whereby miRNAs influence gene expression after SE. Status epilepticus results in transcriptional up-regulation of 100s of genes. miRNAs lie downstream of this and exert influence over protein production and as a result, influence post-injury outcomes such as repair, cell death and reorganization. Such miRNAs represent potential treatment targets to interrupt pathogenesis of damage and long-term consequences (e.g., hyperexcitability).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824358&req=5

Figure 1: (A) Cartoon showing the site and mechanism of miRNA targeting to mRNA. Figure highlights the seven nucleotide “seed” region critical for miRNA binding to the mRNA target. Additional binding also determines specificity and potency. Alignment is facilitated by initial miRNA loading into the RISC which contains Ago2 and GW182 proteins. Binding typically occurs within the 3′UTR. The result is either degradation of the mRNA target or inhibition of translation. (B) Cartoon depicting scheme whereby miRNAs influence gene expression after SE. Status epilepticus results in transcriptional up-regulation of 100s of genes. miRNAs lie downstream of this and exert influence over protein production and as a result, influence post-injury outcomes such as repair, cell death and reorganization. Such miRNAs represent potential treatment targets to interrupt pathogenesis of damage and long-term consequences (e.g., hyperexcitability).
Mentions: MiRNAs control protein output by binding to specific, complementary sequences in target mRNAs of protein-coding genes. MiRNA binding sites are most often found in the 3′untranslated region (UTR) but have also been identified at the 5′end and within the open reading frame (ORF; Bartel, 2009). In mammals, miRNAs usually do not have complete complementarity to the mRNA sequence and therefore do not trigger direct cleavage of the mRNA as occurs with the RNA interference pathway activated by short interfering RNAs (Krol et al., 2010). However, mRNA levels of targets are often reduced by miRNA targeting (Lim et al., 2005; Guo et al., 2010). Targeting involves a 7–8 nucleotide “seed” region within the 5′ end of the miRNA binding to the mRNA via Watson–Crick base-pairing, followed by a variable number of further binding sites (Bartel, 2009; Figure 1A). The molecular machinery driving this process is the RISC which is a multi-protein complex, comprising members of the argonaute family as well as GW182 proteins (Fabian et al., 2010). Ago2 is critical in loading the miRNA and bringing it together with the mRNA target. The effect of miRNA targeting of a mRNA can be inhibition of translation or deadenylation and subsequent degradation, or both (Fabian et al., 2010). RISCs containing miRNA and their targets may also be sequestered in processing (P) bodies, including at synapses, which is reversible, enabling later release of the mRNA for translation (Cougot et al., 2008; Saugstad, 2010).

Bottom Line: Emerging work in animal models has found that SE produces select changes to miRNAs within the brain.Similar changes in over 20 miRNAs have been found in the hippocampus in two or more studies, suggesting conserved miRNA responses after SE.Intracerebral delivery of chemically modified antisense oligonucleotides (antagomirs) has been shown to have potent, specific and long-lasting effects on brain levels of miRNAs.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland Dublin, Ireland.

ABSTRACT
MicroRNA (miRNA) are an important class of non-coding RNA which function as post-transcriptional regulators of gene expression in cells, repressing and fine-tuning protein output. Prolonged seizures (status epilepticus, SE) can cause damage to brain regions such as the hippocampus and result in cognitive deficits and the pathogenesis of epilepsy. Emerging work in animal models has found that SE produces select changes to miRNAs within the brain. Similar changes in over 20 miRNAs have been found in the hippocampus in two or more studies, suggesting conserved miRNA responses after SE. The miRNA changes that accompany SE are predicted to impact levels of multiple proteins involved in neuronal morphology and function, gliosis, neuroinflammation, and cell death. miRNA expression also displays select changes in the blood after SE, supporting blood genomic profiling as potential molecular biomarkers of seizure-damage or epileptogenesis. Intracerebral delivery of chemically modified antisense oligonucleotides (antagomirs) has been shown to have potent, specific and long-lasting effects on brain levels of miRNAs. Targeting miR-34a, miR-132 and miR-184 has been reported to alter seizure-induced neuronal death, whereas targeting miR-134 was neuroprotective, reduced seizure severity during status epilepticus and reduced the later emergence of recurrent spontaneous seizures. These studies support roles for miRNAs in the pathophysiology of status epilepticus and miRNAs may represent novel therapeutic targets to reduce brain injury and epileptogenesis.

No MeSH data available.


Related in: MedlinePlus