Neurofibromin Regulates Seizure Attacks in the Rat Pilocarpine-Induced Model of Epilepsy

Ren, Min; Li, Kunyi; Wang, Dan; Guo, Jiamei; Li, Jing; Yang, Guang; Long, Xianghua; Shen, Wenjing; Hu, Rong; Wang, Xuefeng; Zeng, Kebin

doi:10.1007/s12035-015-9503-9

Cited by 8 publications

(7 citation statements)

References 45 publications

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“…In this case, the loss of gene functions is at least not directly related to mutations in the CDS region but due to abnormal splicing, which would become undetected from conventional mutation screening. It is interesting to note that many of the MEharboring epilepsy-associated genes are typically reported to be dysregulated in TLE patients' brains, for example, SCN1A (Colosimo et al, 2007;Van Poppel et al, 2012;Kasperaviciute et al, 2013), BRD2 (Turnbull et al, 2005), and NF1 (Ren et al, 2016;Gales and Prayson, 2017). Therefore, our data seem to suggest ME-associated abnormal splicing as a novel mechanism contributing to dysregulation of these genes.…”

Section: Discussionmentioning

confidence: 55%

Transcriptome Analysis Reveals Higher Levels of Mobile Element-Associated Abnormal Gene Transcripts in Temporal Lobe Epilepsy Patients

Liang

2021

Front. Genet.

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Mesial temporal lobe epilepsy (MTLE) is the most common form of epilepsy, and temporal lobe epilepsy patients with hippocampal sclerosis (TLE-HS) show worse drug treatment effects and prognosis. TLE has been shown to have a genetic component, but its genetic research has been mostly limited to coding sequences of genes with known association to epilepsy. Representing a major component of the genome, mobile elements (MEs) are believed to contribute to the genetic etiology of epilepsy despite limited research. We analyzed publicly available human RNA-seq-based transcriptome data to determine the role of mobile elements in epilepsy by performing de novo transcriptome assembly, followed by identification of spliced gene transcripts containing mobile element (ME) sequences (ME-transcripts), to compare their frequency across different sample groups. Significantly higher levels of ME-transcripts in hippocampal tissues of epileptic patients, particularly in TLE-HS, were observed. Among ME classes, short interspersed nuclear elements (SINEs) were shown to be the most frequent contributor to ME-transcripts, followed by long interspersed nuclear elements (LINEs) and DNA transposons. These ME sequences almost in all cases represent older MEs normally located in the intron sequences. For protein coding genes, ME sequences were mostly found in the 3′-UTR regions, with a significant portion also in the coding sequences (CDSs), leading to reading frame disruption. Genes associated with ME-transcripts showed enrichment for the mRNA splicing process and an apparent bias in epileptic transcriptomes toward neural- and epilepsy-associated genes. The findings of this study suggest that abnormal splicing involving MEs, leading to loss of functions in critical genes, plays a role in epilepsy, particularly in TLE-HS, thus providing a novel insight into the molecular mechanisms underlying epileptogenesis.

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Section: Discussionmentioning

confidence: 55%

Transcriptome Analysis Reveals Higher Levels of Mobile Element-Associated Abnormal Gene Transcripts in Temporal Lobe Epilepsy Patients

Liang

2021

Front. Genet.

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“…A PubMed/Medline search of these 100 differentially expressed peptides/proteins in Table 3 and Table 4 showed 70% were related to neurological function, 45% to immune/inflammation, 32% to seizures/epilepsy, 24% to ion-channels, and 10% to blood–brain barrier (BBB). Seizure/epilepsy related proteins (shaded cells in Table 3 and Table 4 ) include: SLIT2 (Slit guidance ligand 2 [ 29 ]), EPHB2 (EphrinB receptor 2, [ 30 ]), LAMA2 (Laminin alpha-2, [ 31 ]), ADAM11 (ADAM (A disintegrin and metalloprotease domain 11, [ 32 ]), P2RX7 (Purinergic receptor P2X 7, [ 33 ]), SLC4A4 (Solute carrier family 4 member 4, [ 34 ]), KCNQ2 (Potassium Voltage-Gated Channel Subfamily Q Member 2, [ 9 ]), VWF (von Willebrand factor, [ 35 ]), RYR2 (Ryanodine receptor 2, [ 36 ]), RECK (Reversion Inducing Cysteine Rich Protein With Kazal Motifs, [ 37 ]), ATP7B (ATPase Copper Transporting Beta, [ 38 ]), NF1 (Neurofibromin 1, [ 39 ]), HDC (Histidine Decarboxylase, [ 40 ]). Two other important seizure/epilepsy related proteins in Table 3 and Table 4 are CACNA2D2 (Calcium Voltage-Gated Channel Auxiliary Subunit Alpha2 delta 2, [ 41 ]) and ASTN2 (Astrotactin 2, [ 42 ]).…”

Section: Resultsmentioning

confidence: 99%

Distinguishing and Biochemical Phenotype Analysis of Epilepsy Patients Using a Novel Serum Profiling Platform

et al. 2020

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Diagnosis of non-symptomatic epilepsy includes a history of two or more seizures and brain imaging to rule out structural changes like trauma, tumor, infection. Such analysis can be problematic. It is important to develop capabilities to help identify non-symptomatic epilepsy in order to better monitor and understand the condition. This understanding could lead to improved diagnostics and therapeutics. Serum mass peak profiling was performed using electrospray ionization mass spectrometry (ESI-MS). A comparison of sera mass peaks between epilepsy and control groups was performed via leave one [serum sample] out cross-validation (LOOCV). MS/MS peptide analysis was performed on serum mass peaks to compare epilepsy patient and control groups. LOOCV identified significant differences between the epilepsy patient group and control group (p = 10−22). This value became non-significant (p = 0.10) when the samples were randomly allocated between the groups and reanalyzed by LOOCV. LOOCV was thus able to distinguish a non-symptomatic epilepsy patient group from a control group based on physiological differences and underlying phenotype. MS/MS was able to identify potential peptide/protein changes involved in this epilepsy versus control comparison, with 70% of the top 100 proteins indicating overall neurologic function. Specifically, peptide/protein sera changes suggested neuro-inflammatory, seizure, ion-channel, synapse, and autoimmune pathways changing between epilepsy patients and controls.

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“…Histology and immunohistochemistry were performed as previously described ( 17 ). The brain tissues of the SAH and sham groups were perfused with 4% paraformaldehyde at 48 h post-surgery, post-fixed for 24 h in the same fixative and cryoprotected via 15 and 30% sucrose prior to sectioning in a cryostat at 35-µm thickness.…”

Section: Methodsmentioning

confidence: 99%

Subarachnoid hemorrhage enhances the expression of TDP‑43 in the brain of experimental rats and human subjects

Zuo

Ai-Zakwani

et al. 2018

Exp Ther Med

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The transactive response DNA-binding protein of 43 (TDP-43) may be involved in neurodegenerative disease and in the response to brain injury; however, alterations in the expression of TDP-43 following subarachnoid hemorrhage (SAH) require further investigation. The present study reported a notable elevation in the expression of TDP-43 within the cerebrospinal fluid (CSF) of patients with aneurysmal SAH and increased brain expression of TDP-43 in a rat model of SAH. The TDP-43 protein and a derivative migrated at 43 and 24 kDa, respectively, as observed via the immunoblotting of concentrated CSF samples obtained from patients with SAH; no signal was detected in the CSF from healthy controls. SAH in rats was induced by intravascular suture puncture. The expression levels of TDP-43 in rat cortical lysates following SAH were increased at 0.5 h, peaked at 48 h and remained significantly elevated at 72 h post-injury, compared with sham controls. TDP-43 immunolabeling indication localization within neurons, astrocytes and microglia in the experimental rats. Collectively, the findings of the present study indicated the early involvement of TDP-43 in the brain in response to SAH, and that expression levels of TDP-43 in the CSF may serve as a prognostic biomarker among patients with this condition.

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Neurofibromin Regulates Seizure Attacks in the Rat Pilocarpine-Induced Model of Epilepsy

Cited by 8 publications

References 45 publications

Transcriptome Analysis Reveals Higher Levels of Mobile Element-Associated Abnormal Gene Transcripts in Temporal Lobe Epilepsy Patients

Transcriptome Analysis Reveals Higher Levels of Mobile Element-Associated Abnormal Gene Transcripts in Temporal Lobe Epilepsy Patients

Distinguishing and Biochemical Phenotype Analysis of Epilepsy Patients Using a Novel Serum Profiling Platform

Subarachnoid hemorrhage enhances the expression of TDP‑43 in the brain of experimental rats and human subjects

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