Dynamic miRNA changes during the process of epileptogenesis in an infantile and adult-onset model

Bencúrová, Petra; Baloun, Jiří; Hynšt, Jakub; Oppelt, Jan; Kubová, Hana; Pospı́šilová, Šárka; Brázdil, Milan

doi:10.1038/s41598-021-89084-9

Cited by 14 publications

(13 citation statements)

References 67 publications

(38 reference statements)

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“…Together, these results indicate that increased activity leads to increases and decreases in specific NSPs. Decreased NSPs may arise by decreasing transcript levels ( Raab-Graham and Niere, 2017 ; Dong et al, 2020 ), for instance, downstream of activity-induced expression of transcriptional repressors ( Ashok et al, 2020 ; Dong et al, 2020 ), by miRNA-mediated mechanisms ( Henshall et al, 2016 ; Bencurova et al, 2021 ; Zolboot et al, 2021 ) or by activity-induced degradation of NSPs. Recent studies identified a neuronal membrane-associated proteosome that degrades activity-induced NSPs ( Ramachandran and Margolis, 2017 ; Ramachandran et al, 2018 ; He et al, 2022 ) and is required for behavioral plasticity ( He et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Activity-Induced Cortical Glutamatergic Neuron Nascent Proteins

et al. 2022

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Neuronal activity initiates signaling cascades that culminate in diverse outcomes including structural and functional neuronal plasticity, and metabolic changes. While studies have revealed activity-dependent neuronal cell type-specific transcriptional changes, unbiased quantitative analysis of cell-specific activity-induced dynamics in newly synthesized proteins (NSPs) synthesis in vivo has been complicated by cellular heterogeneity and a relatively low abundance of NSPs within the proteome in the brain. Here we combined targeted expression of mutant MetRS (methionine tRNA synthetase) in genetically defined cortical glutamatergic neurons with tight temporal control of treatment with the noncanonical amino acid, azidonorleucine, to biotinylate NSPs within a short period after pharmacologically induced seizure in male and female mice. By purifying peptides tagged with heavy or light biotin-alkynes and using direct tandem mass spectrometry detection of biotinylated peptides, we quantified activity-induced changes in cortical glutamatergic neuron NSPs. Seizure triggered significant changes in ∼300 NSPs, 33% of which were decreased by seizure. Proteins mediating excitatory and inhibitory synaptic plasticity, including SynGAP1, Pak3, GEPH1, Copine-6, and collybistin, and DNA and chromatin remodeling proteins, including Rad21, Smarca2, and Ddb1, are differentially synthesized in response to activity. Proteins likely to play homeostatic roles in response to activity, such as regulators of proteastasis, intracellular ion control, and cytoskeleton remodeling proteins, are activity induced. Conversely, seizure decreased newly synthetized NCAM, among others, suggesting that seizure induced degradation. Overall, we identified quantitative changes in the activity-induced nascent proteome from genetically defined cortical glutamatergic neurons as a strategy to discover downstream mediators of neuronal plasticity and generate hypotheses regarding their function. SIGNIFICANCE STATEMENT Activity-induced neuronal and synaptic plasticity are mediated by changes in the protein landscape, including changes in the activity-induced newly synthesized proteins; however, identifying neuronal cell type-specific nascent proteome dynamics in the intact brain has been technically challenging. We conducted an unbiased proteomic screen from which we identified significant activity-induced changes in ∼300 newly synthesized proteins in genetically defined cortical glutamatergic neurons within 20 h after pharmacologically induced seizure. Bioinformatic analysis of the dynamic nascent proteome indicates that the newly synthesized proteins play diverse roles in excitatory and inhibitory synaptic plasticity, chromatin remodeling, homeostatic mechanisms, and proteasomal and metabolic functions, extending our understanding of the diversity of plasticity mechanisms.

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Section: Discussionmentioning

confidence: 99%

Activity-Induced Cortical Glutamatergic Neuron Nascent Proteins

et al. 2022

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“…Notably, altered levels of miR-335-5p appear to vary between models, consistent with temporally-and activitycontrolled miRNA expression. Indeed, miR-335-5p levels were upregulated in the hippocampus in several rodent models of TLE (34)(35)(36), butdownregulation has also been reported (33,37,38). Levels of miR-335-5p were downregulated in resected hippocampal tissue from people with TLE with hippocampal sclerosis (34).…”

Section: Discussionmentioning

confidence: 91%

MicroRNA-335-5p suppresses voltage-gated sodium channel expression and may be a target for seizure control

Heiland

Connolly

Nguyen

et al. 2022

Preprint

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There remains an urgent need for new therapies for drug-resistant epilepsy (DRE). Sodium channel blockers are effective for seizure control in common forms of epilepsy, but loss of sodium channel function underlies some genetic forms of epilepsy. Approaches that provide bi-directional control of sodium channel expression are needed. MicroRNAs (miRNA) are small non-coding RNAs which negatively regulate gene expression. Here, we show that genome-wide miRNA screening of hippocampal tissue from a rat epilepsy model, mice treated with the novel anti-seizure medicine cannabidiol (CBD) and plasma from patients with DRE, converge on a single target, miR-335-5p. Pathway analysis on predicted and validated miR-335-5p targets identified multiple voltage-gated sodium channels (VGSCs). Intracerebroventricular injection of antisense oligonucleotides against miR-335-5p resulted in upregulation of Scn1a, Scn2a and Scn3a in the mouse brain and an increased action potential rising phase and greater excitability of hippocampal pyramidal neurons in brain slice recordings, consistent with VGSCs as functional targets of miR-335-5p. Blocking of miR-335-5p also increased voltage-gated sodium currents in human iPSC-derived neurons. Inhibition of miR-335-5p increased susceptibility to tonic-clonic seizures in the pentylenetetrazole seizure model, whereas AAV9-mediated overexpression of miR-335-5p reduced seizure severity and improved survival. These studies suggest modulation of miR-335-5p may be a means to regulate VGSCs and affect brain excitability and seizures. Changes to miR-335-5p may reflect compensatory mechanisms to control excitability and could provide new biomarker or therapeutic strategies for different types of drug-resistant epilepsy.

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“…Previous studies have demonstrated that the expression of certain miRNAs shows dramatic temporal changes as pathologic condition progresses [ 69 , 70 , 71 ]. Furthermore, the expression of a certain miRNA can be also bidirectional depending on the intensity of the same stimulation.…”

Section: Discussionmentioning

confidence: 99%

Suppressing Pyroptosis Augments Post-Transplant Survival of Stem Cells and Cardiac Function Following Ischemic Injury

Lee

Jeong

et al. 2021

IJMS

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The acute demise of stem cells following transplantation significantly compromises the efficacy of stem cell-based cell therapeutics for infarcted hearts. As the stem cells transplanted into the damaged heart are readily exposed to the hostile environment, it can be assumed that the acute death of the transplanted stem cells is also inflicted by the same environmental cues that caused massive death of the host cardiac cells. Pyroptosis, a highly inflammatory form of programmed cell death, has been added to the list of important cell death mechanisms in the damaged heart. However, unlike the well-established cell death mechanisms such as necrosis or apoptosis, the exact role and significance of pyroptosis in the acute death of transplanted stem cells have not been explored in depth. In the present study, we found that M1 macrophages mediate the pyroptosis in the ischemia/reperfusion (I/R) injured hearts and identified miRNA-762 as an important regulator of interleukin 1b production and subsequent pyroptosis. Delivery of exogenous miRNA-762 prior to transplantation significantly increased the post-transplant survival of stem cells and also significantly ameliorated cardiac fibrosis and heart functions following I/R injury. Our data strongly suggest that suppressing pyroptosis can be an effective adjuvant strategy to enhance the efficacy of stem cell-based therapeutics for diseased hearts.

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Dynamic miRNA changes during the process of epileptogenesis in an infantile and adult-onset model

Cited by 14 publications

References 67 publications

Activity-Induced Cortical Glutamatergic Neuron Nascent Proteins

Activity-Induced Cortical Glutamatergic Neuron Nascent Proteins

MicroRNA-335-5p suppresses voltage-gated sodium channel expression and may be a target for seizure control

Suppressing Pyroptosis Augments Post-Transplant Survival of Stem Cells and Cardiac Function Following Ischemic Injury

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