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Ortrud K Steinlein - One of the best experts on this subject based on the ideXlab platform.
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Pleiotropic functional effects of the first epilepsy-associated mutation in the human CHRNA2 gene
FEBS Letters, 2009Co-Authors: Jean-charles Hoda, Mario Wanischeck, Daniel Bertrand, Ortrud K SteinleinAbstract:Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) can be caused by mutations in the neuronal nicotinic acetylcholine receptor (nAChR) subunit genes CHRNA4 and CHRNB2. Recently, a point mutation (alpha2-I279N) associated with sleep-related epilepsy has been described in a third nAChR gene, CHRNA2. We demonstrate here that alpha2-I279N can be co-expressed with the major structural subunit CHRNB2. alpha2-I279N causes a marked gain-of-function effect and displays a distinct biopharmacological profile, including markedly reduced inhibition by carbamazepine and increased nicotine sensitivity.
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A major role of the nicotinic acetylcholine receptor gene CHRNA2 in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is unlikely
Neuroscience Letters, 2007Co-Authors: Daniel Bertrand, Ortrud K SteinleinAbstract:Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is known to be caused by mutations in the transmembrane regions of the neuronal nicotinic acetylcholine receptor (nAChR) genes CHRNA4 and CHRNB2. A third nAChR gene, CHRNA2, has been recently reported as mutated in an Italian family with nocturnal frontal lobe epilepsy, nocturnal wandering and ictal fear. We have now evaluated the role of CHRNA2 in families with "classical" ADNFLE. Mutation screening was performed in 47 families by amplification and subsequent sequencing of part of CHRNA2 exon 6 containing transmembrane regions 1-3. Detected variants were tested in a case-control association study. No mutations were identified in the parts of CHRNA2 that contribute to the ion pore. Sequencing identified a novel synonymous nucleotide exchange (c.771C/T) that was also present in two of 78 controls and is therefore likely to be non-pathogenic. The absence of mutations in our sample of 47 families renders a major role of CHRNA2 in ADNFLE unlikely.
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The CHRNB2 mutation I312M is associated with epilepsy and distinct memory deficits.
Neurobiology of Disease, 2005Co-Authors: Daniel Bertrand, Sonia Bertrand, Frances Elmslie, Elaine Hughes, John Q. Trounce, Thomas Sander, Ortrud K SteinleinAbstract:Mutations in nAChRs are found in a rare form of nocturnal frontal lobe epilepsy (ADNFLE). Previously, some nAChR mutations have been described that are associated with additional neurological features such as psychiatric disorders or cognitive defects. Here, we report a new CHRNB2 mutation located in transmembrane region 3 (M3), outside the known ADNFLE mutation cluster. The CHRNB2 mutation I312M, which occurred de novo in twins, markedly increases the receptor's sensitivity to acetylcholine. Phenotypically, the mutation is associated not only with typical ADNFLE, but also with distinct deficits in memory. The cognitive problems are most obvious in tasks requiring the organization and storage of verbal information.
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Schizophrenia, psychotic illness and other psychiatric symptoms in families with autosomal dominant nocturnal frontal lobe epilepsy caused by different mutations.
Psychiatric Genetics, 2003Co-Authors: Andres Magnusson, Eystein Stordal, Eylert Brodtkorb, Ortrud K SteinleinAbstract:ObjectivesAutosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by a strong family history of epileptic seizures, which predominantly occur during sleep. ADNFLE has been associated with mutations in two genes coding for the nicotinic acetylcholine receptor (CHRNA4 and CHRNB2).
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the structures of the human neuronal nicotinic acetylcholine receptor β2 and α3 subunit genes CHRNB2 and chrna3
Human Genetics, 1998Co-Authors: Nicole Rempel, Sibilla Heyers, E Sleegers, Hartmut Engels, Ortrud K SteinleinAbstract:The α4-subunit gene (CHRNA4) of the neuronal nicotinic acetylcholine receptor (nAChR) subunit family has recently been identified in two families as the gene responsible for autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), a rare monogenic idiopathic epilepsy. As a result of this finding, other subunits of the neuronal nAChR gene family are being considered as candidate genes for ADNFLE in families not linked to CHRNA4 and for other idiopathic epilepsies. α4-subunitsoften assemble together with β2-subunits (gene symbol CHRNB2) to build heteromeric nAChRs. The gene encoding another abundant AChR subunit, the α3-subunit gene (CHRNA3), is present with those encoding two other subunits, CHRNB4 and CHRNA5, in a gene cluster whose functional role is still unclear. Here we provide the information on the genomic structures of both the CHRNB2 and the CHRNA3 genes that is necessary for comprehensive mutational analyses, and we refine the genomic assignment of CHRNB2 on chromosome 1.
Marissa A. Ehringer - One of the best experts on this subject based on the ideXlab platform.
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Alternative CHRNB4 3′-UTRs Mediate the Allelic Effects of SNP rs1948 on Gene Expression
PLoS ONE, 2013Co-Authors: Xavier Gallego, Jerry A Stitzel, Ryan J. Cox, James R. Laughlin, Marissa A. EhringerAbstract:Common genetic factors strongly contribute to both nicotine, the main addictive component of tobacco, and alcohol use. Several lines of evidence suggest nicotinic acetylcholine receptors as common sites of action for nicotine and alcohol. Specifically, rs1948, a single-nucleotide polymorphism (SNP) located in the CHRNB4 3′-untranslated region (UTR), has been associated to early age of initiation for both alcohol and tobacco use. To determine the allelic effects of rs1948 on gene expression, two rs1948-containing sequences of different lengths corresponding to the CHRNB4 3′-UTR were cloned into pGL3-promoter luciferase reporter vectors. Data obtained showed that the allelic effects of SNP rs1948 on luciferase expression are mediated by the length and species of transcripts generated. In addition, it was found that miR-3157 increased the overall luciferase expression while miR-138, a microRNA known to play a role in neuroadaptation to drug abuse, decreased luciferase expression when compared to basal conditions. These findings demonstrate the importance of SNP rs1948 on the regulation of CHRNB4 expression and provide the first evidence of CHRNB4 down-regulation by miR-138.
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alternative chrnb4 3 utrs mediate the allelic effects of snp rs1948 on gene expression
PLOS ONE, 2013Co-Authors: Xavier Gallego, Jerry A Stitzel, Ryan J. Cox, James R. Laughlin, Marissa A. EhringerAbstract:Common genetic factors strongly contribute to both nicotine, the main addictive component of tobacco, and alcohol use. Several lines of evidence suggest nicotinic acetylcholine receptors as common sites of action for nicotine and alcohol. Specifically, rs1948, a single-nucleotide polymorphism (SNP) located in the CHRNB4 3′-untranslated region (UTR), has been associated to early age of initiation for both alcohol and tobacco use. To determine the allelic effects of rs1948 on gene expression, two rs1948-containing sequences of different lengths corresponding to the CHRNB4 3′-UTR were cloned into pGL3-promoter luciferase reporter vectors. Data obtained showed that the allelic effects of SNP rs1948 on luciferase expression are mediated by the length and species of transcripts generated. In addition, it was found that miR-3157 increased the overall luciferase expression while miR-138, a microRNA known to play a role in neuroadaptation to drug abuse, decreased luciferase expression when compared to basal conditions. These findings demonstrate the importance of SNP rs1948 on the regulation of CHRNB4 expression and provide the first evidence of CHRNB4 down-regulation by miR-138.
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CHRNB2 promoter region: association with subjective effects to nicotine and gene expression differences
Genes Brain and Behavior, 2010Co-Authors: Nicole R Hoft, Jerry A Stitzel, Kent E. Hutchison, Marissa A. EhringerAbstract:Smoking behavior is a complex, which includes multiple stages in the progression from experimentation to continued use and dependence. The experience of subjective effects, such as dizziness, euphoria, heart pounding, nausea and high, have been associated with varying degrees of persistence and subsequent abuse/dependence of marijuana, cocaine, tobacco and alcohol (Grant et al. 2005, Wagner & Anthony 2002). Previous studies have reported associations between neuronal nicotinic receptor (CHRN) genes and subjective effects to nicotine. We sought to replicate and expand this work by examining eight single nucleotide polymorphisms (SNPs) in a sample of adult smokers (n = 316) who reported subjective effects following cigarette smoking in a controlled laboratory environment. Two SNPs each in the CHRNB2, CHRNB3, CHRNA6 and CHRNA4 genes were examined. A significant association was found between two SNPs and physical effects reported after smoking the first experimental cigarette. SNP rs2072658 is upstream of CHRNB2 (P-value = 0.0046) and rs2229959 is a synonymous change in exon 5 of CHRNA4 (P value = 0.0051). We also examined possible functional relevance of SNP rs2072658 using an in vitro gene expression assay. These studies provided evidence that the minor allele of rs2072658 may lead to decreased gene expression, using two separate cell lines, P19 and SH-SY5Y (18% P < 0.001 and 26% P < 0.001 respectively). The human genetic study and functional assays suggest that variation in the promoter region of CHRNB2 gene may be important in mediating levels of expression of the β2 nicotinic receptor subunit, which may be associated with variation in subjective response to nicotine.
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Association of the neuronal nicotinic receptor beta2 subunit gene (CHRNB2) with subjective responses to alcohol and nicotine.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2007Co-Authors: Marissa A. Ehringer, Christian J. Hopfer, John K Hewitt, Allan C. Collins, Robin P. Corley, Jeffrey M. Lessem, Hilary V. Clegg, Kenneth Krauter, Thomas Crowley, Soo Hyun RheeAbstract:Nicotine addiction and alcohol dependence are highly comorbid disorders that are likely to share overlapping genetic components. We have examined two neuronal nicotinic receptor subunit genes (CHRNA4 and CHRNB2) for possible associations with nicotine and alcohol phenotypes, including measures of frequency of use and measures of initial subjective response in the period shortly after first using the drugs. The subjects were 1,068 ethnically diverse young adults participating in ongoing longitudinal studies of adolescent drug behaviors at the University of Colorado, representing both clinical and community samples. Analysis of six SNPs in the CHRNA4 gene provided modest support for an association with past 6 month use of alcohol in Caucasians (three SNPs with P < 0.08), but no evidence for an association with tobacco and CHRNA4 was detected. However, a SNP (rs2072658) located immediately upstream of CHRNB2 was associated with the initial subjective response to both alcohol and tobacco. This study provides the first evidence for association between the CHRNB2 gene and nicotine- and alcohol-related phenotypes, and suggests that polymorphisms in CHRNB2 may be important in mediating early responses to nicotine and alcohol.
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Association of the neuronal nicotinic receptor β2 subunit gene (CHRNB2) with subjective responses to alcohol and nicotine
American Journal of Medical Genetics, 2007Co-Authors: Marissa A. Ehringer, Christian J. Hopfer, Thomas J. Crowley, John K Hewitt, Allan C. Collins, Robin P. Corley, Jeffrey M. Lessem, Hilary V. Clegg, Kenneth Krauter, Soo Hyun RheeAbstract:Nicotine addiction and alcohol dependence are highly comorbid disorders that are likely to share overlapping genetic components. We have examined two neuronal nicotinic receptor subunit genes (CHRNA4 and CHRNB2) for possible associations with nicotine and alcohol phenotypes, including measures of frequency of use and measures of initial subjective response in the period shortly after first using the drugs. The subjects were 1,068 ethnically diverse young adults participating in ongoing longitudinal studies of adolescent drug behaviors at the University of Colorado, representing both clinical and community samples. Analysis of six SNPs in the CHRNA4 gene provided modest support for an association with past 6 month use of alcohol in Caucasians (three SNPs with P < 0.08), but no evidence for an association with tobacco and CHRNA4 was detected. However, a SNP (rs2072658) located immediately upstream of CHRNB2 was associated with the initial subjective response to both alcohol and tobacco. This study provides the first evidence for association between the CHRNB2 gene and nicotine- and alcohol-related phenotypes, and suggests that polymorphisms in CHRNB2 may be important in mediating early responses to nicotine and alcohol.
Mouwang Zhou - One of the best experts on this subject based on the ideXlab platform.
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Transcriptomic analysis of α-synuclein knockdown after T3 spinal cord injury in rats.
BMC Genomics, 2019Co-Authors: Hong Zeng, Nan Liu, Yan-yan Yang, Hua-yi Xing, Liu Xiaoxie, Mouwang ZhouAbstract:Endogenous α-synuclein (α-Syn) is involved in many pathophysiological processes in the secondary injury stage after acute spinal cord injury (SCI), and the mechanism governing these functions has not been thoroughly elucidated to date. This research aims to characterize the effect of α-Syn knockdown on transcriptional levels after SCI and to determine the mechanisms underlying α-Syn activity based on RNA-seq. The establishment of a rat model of lentiviral vector-mediated knockdown of α-Syn in Sprague-Dawley rats with T3 spinal cord contusion (LV_SCI group). The results of the RNA-seq analysis showed that there were 337 differentially expressed genes (DEGs) between the SCI group and the LV_SCI group, and 153 DEGs specific to LV_SCI between the (SCI vs LV_SCI) and (SCI vs CON) comparisons. The top 20 biological transition terms were identified by Gene ontology (GO) analysis. The Kyoto Gene and Genomic Encyclopedia (KEGG) analysis showed that the LV_SCI group significantly upregulated the cholinergic synaptic & nicotine addiction and the neuroactive ligand receptor interaction signaling pathway. Enriched chord analysis analyzes key genes. Further cluster analysis, gene and protein interaction network analysis and RT-qPCR results showed that Chrm2 and CHRNB2 together significantly in both pathways. The proliferation of muscarinic cholinergic receptor subtype 2 (Chrm2) and nicotinic cholinergic receptor subtype β2 (CHRNB2), and the neurogenesis were elevated in the injury site of LV_SCI group by immunofluorescence. Further by subcellular localization, the LV_SCI group enhanced the expression of CHRNB2 at the cell membrane. Knockdown of α-Syn after SCI enhance motor function and promote neurogenesis probably through enhancing cholinergic signaling pathways and neuroreceptor interactions. This study not only further clarifies the understanding of the mechanism of knockdown of α-Syn on SCI but also helps to guide the treatment strategy for SCI.
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Transcriptomic analysis of α-synuclein knockdown after T3 spinal cord injury in rats
2019Co-Authors: Hong Zeng, Nan Liu, Yan-yan Yang, Hua-yi Xing, Xiao-xie Liu, Mouwang ZhouAbstract:Abstract Abstract Background Endogenous α-synuclein (α-Syn) is involved in many pathophysiological processes in the secondary injury stage after acute spinal cord injury (SCI), and the mechanism governing these functions has not been thoroughly elucidated to date. This research aims to characterize the effect of α-Syn knockdown on transcriptional levels after SCI and to determine the mechanisms underlying α-Syn activity based on RNA-seq. Result The establishment of a rat model of lentiviral vector-mediated knockdown of α-Syn in Sprague-Dawley rats with T3 spinal cord contusion (LV_SCI group). The results of the RNA-seq analysis showed that there were 337 differentially expressed genes (DEGs) between the SCI group and the LV_SCI group, and 153 DEGs specific to LV_SCI between the (SCI vs LV_SCI) and (SCI vs CON) comparisons . The top 20 biological transition terms were identified by Gene ontology (GO) analysis. The Kyoto Gene and Genomic Encyclopedia (KEGG) analysis showed that the LV_SCI group significantly upregulated the cholinergic synaptic & nicotine addiction and the neuroactive ligand receptor interaction signaling pathway. Enriched chord analysis analyzes key genes. Further cluster analysis, gene and protein interaction network analysis and RT-qPCR results showed that Chrm2 and CHRNB2 together significantly in both pathways. The proliferation of muscarinic cholinergic receptor subtype 2 (Chrm2) and nicotinic cholinergic receptor subtype β2 (CHRNB2), and the neurogenesis were elevated in the injury site of LV_SCI group by immunofluorescence. Further by subcellular localization, the LV_SCI group enhanced the expression of CHRNB2 at the cell membrane. Conclusion Knockdown of α-Syn after SCI enhance motor function and promote neurogenesis probably through enhancing cholinergic signaling pathways and neuroreceptor interactions. This study not only further clarifies the understanding of the mechanism of knockdown of α-Syn on SCI but also helps to guide the treatment strategy for SCI.
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Transcriptomic analysis of α-synuclein knockdown after T3 spinal cord injury in rats
2019Co-Authors: Hong Zeng, Nan Liu, Yan-yan Yang, Hua-yi Xing, Xiao-xie Liu, Mouwang ZhouAbstract:Abstract Abstract Background Endogenous α-synuclein (α-Syn) is involved in many pathophysiological processes in the secondary injury stage after acute spinal cord injury (SCI), and the mechanism governing these functions has not been thoroughly elucidated to date. This research aims to characterize the effect of α-Syn knockdown on transcriptional levels after SCI and to determine the mechanisms underlying α-Syn activity based on RNA-seq. Result The establishment of a rat model of lentiviral vector-mediated knockdown of α-Syn in Sprague-Dawley rats with T3 spinal cord contusion. The results of the RNA-SEQ analysis showed that there were 191 differentially expressed genes (DEGs) between the SCI group and the LV_SCI group, and 96 DEGs in the LV_SCI group compared with the sham operation group (CON group). The top 20 biological transition terms were identified by Gene ontology (GO) analysis. The Kyoto Gene and Genomic Encyclopedia (KEGG) analysis showed that the LV_SCI group significantly up-regulated the cholinergic synaptic pathway and the neuroactive ligand receptor interaction signaling pathway. Enriched chord analysis analyzes key genes. Further cluster analysis, gene and protein interaction network analysis showed that Chrm2 and CHRNB2 together observed the LV_SCI group to promote the proliferation of Chrm2 and CHRNB2 and the neurogenesis of the injury site by immunofluorescence. Further by subcellular localization, the LV_SCI group enhanced the expression of CHRNB2 at the cell membrane and cell junction. Conclusion Knockdown of α-synuclein after spinal cord injury enhance motor function and promote neurogenesis probably through enhancing cholinergic signaling pathways and neuroreceptor interactions. This study not only further clarifies the understanding of the mechanism of knockdown of α-synuclein on SCI but also helps to guide the treatment strategy for SCI.
Maria Luisa Tenchini - One of the best experts on this subject based on the ideXlab platform.
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CHRNA2 mutations are rare in the NFLE population: evaluation of a large cohort of Italian patients
Sleep Medicine, 2009Co-Authors: Romina Combi, Luigi Ferini-strambi, Maria Luisa TenchiniAbstract:Abstract Objective Forty-six nocturnal frontal lobe epilepsy (NFLE) patients (in which the involvement of the CHRNA4 and CHRNB2 genes coding for neuronal nicotinic acetylcholine receptor (nAChRs) subunits associated to the disease were previously excluded) were analyzed for the presence of mutations in the CHRNA2 gene coding for the alpha2 subunit of the same receptor, which has been recently associated with the disease. Methods Mutational screening was performed by sequencing two polymerase chain reaction-amplified CHRNA2 DNA fragments, spanning the whole exon 6 and exon 7, respectively, which code for ∼75% of the mature protein and contain all four transmembrane domains contributing to the ion pore. Results No mutations were identified in the analyzed region of CHRNA2 . Conclusions These data demonstrate the rarity of the identified CHRNA2 mutations in NFLE patients, supporting the recently reported hypothesis of a restricted role for this gene in the disease.
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Exclusion of linkage of nine neuronal nicotinic acetylcholine receptor subunit genes expressed in brain in autosomal dominant nocturnal frontal lobe epilepsy in four unrelated families
Journal of Neurology, 2002Co-Authors: Maria Teresa Bonati, Massimo Malcovati, Stefano Duga, Rosanna Asselta, Romina Combi, Leda Dalprà, Luigi Ferini-strambi, Alessandro Oldani, Marco Zucconi, Maria Luisa TenchiniAbstract:Members of the ligand-gated neuronal nicotinic acetylcholine receptor (nAChR) gene family ( CHRNA4 and CHRNB2 , coding for the α4 and β2 subunits, respectively) are involved in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). However, ADNFLE is genetically heterogeneous and mutations in CHRNA4 and CHRNB2 account for only a minority of ADNFLE cases. Additional nAChR subunits expressed in the brain are candidates for this epilepsy. The involvement of all genes coding for brain-expressed nAChR subunits, with known chromosome localization ( CHRNB2 , 1q21; CHRNA2 , 8p21; CHRNA6 , CHRNB3 , 8p11.2; CHRNA7 , 15q14; CHRNA5/A3/B4 , 15q24 and CHRNA4 , 20q13.2) was investigated in four unrelated ADNFLE Italian families for at least three generations. Families were selected on the basis of anamnestic and videopolysomnographic analyses. Individuals were typed for polymorphic markers located in the above mentioned chromosome regions. Linkage and mutation analyses were performed. In none of the families was linkage between ADNFLE and the analysed chromosome regions detected. These findings support the hypothesis that genes different from those coding for α2-7 and β2-4 neuronal nAChR subunits could be responsible for ADNFLE.
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Mutational Analysis of Nicotinic Acetylcholine Receptor β2 Subunit Gene (CHRNB2) in a Representative Cohort of Italian Probands Affected by Autosomal Dominant Nocturnal Frontal Lobe Epilepsy
Epilepsia, 2002Co-Authors: Stefano Duga, Massimo Malcovati, Rosanna Asselta, Maria Teresa Bonati, Leda Dalprà, Luigi Ferini-strambi, Alessandro Oldani, Marco Zucconi, Maria Luisa TenchiniAbstract:Summary: Twenty-four autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) probands were analyzed for the presence of V287L and V287M mutations in the CHRNB2 gene, which have been recently associated with the disease. In all patients, the involvement of the two additional loci reported as being associated with ADNFLE (CHRNA4 gene and chromosome 15q24 region) had been previously excluded. Mutational screening was performed by sequencing a polymerase chain reaction–amplified CHRNB2 DNA fragment, spanning the whole exon 5, which contains the V287L and V287M mutations and codes for ∼65% of the mature protein. In none of the patients were mutations in the analyzed region of CHRNB2 found. These data, obtained in the largest ADNFLE cohort so far analyzed, demonstrate the rarity of the identified CHRNB2 mutations in ADNFLE patients.
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Characterization of the genomic structure of the human neuronal nicotinic acetylcholine receptor CHRNA5/A3/B4 gene cluster and identification of novel intragenic polymorphisms
Journal of Human Genetics, 2001Co-Authors: Stefano Duga, Massimo Malcovati, Rosanna Asselta, Giulia Solda, Maria Teresa Bonati, Leda Dalprà, Maria Luisa TenchiniAbstract:Genes coding for the α5, α3, and β4 subunits (CHRNA5, CHRNA3, and CHRNB4) of the neuronal nicotinic acetylcholine receptors (nAChRs) are clustered on chromosome 15q24. Linkage of this chromosomal region to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), an idiopathic partial epilepsy, was reported in one family. Moreover, mutations in other neuronal nAChR subunit genes coding for the α4 (CHRNA4) and the β2 (CHRNB2) subunits were associated with ADNFLE. Apart from the exon-intron structure of CHRNA3, the geno-mic organization of this gene cluster was unknown, making comprehensive mutational analyses impossible. The genomic structure of CHRNA5 and CHRNB4 is here reported. Moreover, two hitherto unknown introns were identified within the 3′ untranslated region of CHRNA3, causing a partial tail-to-tail overlap with CHRNA5. Four novel intragenic polymorphisms were identified and characterized in the cluster.
Hong Zeng - One of the best experts on this subject based on the ideXlab platform.
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Transcriptomic analysis of α-synuclein knockdown after T3 spinal cord injury in rats.
BMC Genomics, 2019Co-Authors: Hong Zeng, Nan Liu, Yan-yan Yang, Hua-yi Xing, Liu Xiaoxie, Mouwang ZhouAbstract:Endogenous α-synuclein (α-Syn) is involved in many pathophysiological processes in the secondary injury stage after acute spinal cord injury (SCI), and the mechanism governing these functions has not been thoroughly elucidated to date. This research aims to characterize the effect of α-Syn knockdown on transcriptional levels after SCI and to determine the mechanisms underlying α-Syn activity based on RNA-seq. The establishment of a rat model of lentiviral vector-mediated knockdown of α-Syn in Sprague-Dawley rats with T3 spinal cord contusion (LV_SCI group). The results of the RNA-seq analysis showed that there were 337 differentially expressed genes (DEGs) between the SCI group and the LV_SCI group, and 153 DEGs specific to LV_SCI between the (SCI vs LV_SCI) and (SCI vs CON) comparisons. The top 20 biological transition terms were identified by Gene ontology (GO) analysis. The Kyoto Gene and Genomic Encyclopedia (KEGG) analysis showed that the LV_SCI group significantly upregulated the cholinergic synaptic & nicotine addiction and the neuroactive ligand receptor interaction signaling pathway. Enriched chord analysis analyzes key genes. Further cluster analysis, gene and protein interaction network analysis and RT-qPCR results showed that Chrm2 and CHRNB2 together significantly in both pathways. The proliferation of muscarinic cholinergic receptor subtype 2 (Chrm2) and nicotinic cholinergic receptor subtype β2 (CHRNB2), and the neurogenesis were elevated in the injury site of LV_SCI group by immunofluorescence. Further by subcellular localization, the LV_SCI group enhanced the expression of CHRNB2 at the cell membrane. Knockdown of α-Syn after SCI enhance motor function and promote neurogenesis probably through enhancing cholinergic signaling pathways and neuroreceptor interactions. This study not only further clarifies the understanding of the mechanism of knockdown of α-Syn on SCI but also helps to guide the treatment strategy for SCI.
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Transcriptomic analysis of α-synuclein knockdown after T3 spinal cord injury in rats
2019Co-Authors: Hong Zeng, Nan Liu, Yan-yan Yang, Hua-yi Xing, Xiao-xie Liu, Mouwang ZhouAbstract:Abstract Abstract Background Endogenous α-synuclein (α-Syn) is involved in many pathophysiological processes in the secondary injury stage after acute spinal cord injury (SCI), and the mechanism governing these functions has not been thoroughly elucidated to date. This research aims to characterize the effect of α-Syn knockdown on transcriptional levels after SCI and to determine the mechanisms underlying α-Syn activity based on RNA-seq. Result The establishment of a rat model of lentiviral vector-mediated knockdown of α-Syn in Sprague-Dawley rats with T3 spinal cord contusion (LV_SCI group). The results of the RNA-seq analysis showed that there were 337 differentially expressed genes (DEGs) between the SCI group and the LV_SCI group, and 153 DEGs specific to LV_SCI between the (SCI vs LV_SCI) and (SCI vs CON) comparisons . The top 20 biological transition terms were identified by Gene ontology (GO) analysis. The Kyoto Gene and Genomic Encyclopedia (KEGG) analysis showed that the LV_SCI group significantly upregulated the cholinergic synaptic & nicotine addiction and the neuroactive ligand receptor interaction signaling pathway. Enriched chord analysis analyzes key genes. Further cluster analysis, gene and protein interaction network analysis and RT-qPCR results showed that Chrm2 and CHRNB2 together significantly in both pathways. The proliferation of muscarinic cholinergic receptor subtype 2 (Chrm2) and nicotinic cholinergic receptor subtype β2 (CHRNB2), and the neurogenesis were elevated in the injury site of LV_SCI group by immunofluorescence. Further by subcellular localization, the LV_SCI group enhanced the expression of CHRNB2 at the cell membrane. Conclusion Knockdown of α-Syn after SCI enhance motor function and promote neurogenesis probably through enhancing cholinergic signaling pathways and neuroreceptor interactions. This study not only further clarifies the understanding of the mechanism of knockdown of α-Syn on SCI but also helps to guide the treatment strategy for SCI.
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Transcriptomic analysis of α-synuclein knockdown after T3 spinal cord injury in rats
2019Co-Authors: Hong Zeng, Nan Liu, Yan-yan Yang, Hua-yi Xing, Xiao-xie Liu, Mouwang ZhouAbstract:Abstract Abstract Background Endogenous α-synuclein (α-Syn) is involved in many pathophysiological processes in the secondary injury stage after acute spinal cord injury (SCI), and the mechanism governing these functions has not been thoroughly elucidated to date. This research aims to characterize the effect of α-Syn knockdown on transcriptional levels after SCI and to determine the mechanisms underlying α-Syn activity based on RNA-seq. Result The establishment of a rat model of lentiviral vector-mediated knockdown of α-Syn in Sprague-Dawley rats with T3 spinal cord contusion. The results of the RNA-SEQ analysis showed that there were 191 differentially expressed genes (DEGs) between the SCI group and the LV_SCI group, and 96 DEGs in the LV_SCI group compared with the sham operation group (CON group). The top 20 biological transition terms were identified by Gene ontology (GO) analysis. The Kyoto Gene and Genomic Encyclopedia (KEGG) analysis showed that the LV_SCI group significantly up-regulated the cholinergic synaptic pathway and the neuroactive ligand receptor interaction signaling pathway. Enriched chord analysis analyzes key genes. Further cluster analysis, gene and protein interaction network analysis showed that Chrm2 and CHRNB2 together observed the LV_SCI group to promote the proliferation of Chrm2 and CHRNB2 and the neurogenesis of the injury site by immunofluorescence. Further by subcellular localization, the LV_SCI group enhanced the expression of CHRNB2 at the cell membrane and cell junction. Conclusion Knockdown of α-synuclein after spinal cord injury enhance motor function and promote neurogenesis probably through enhancing cholinergic signaling pathways and neuroreceptor interactions. This study not only further clarifies the understanding of the mechanism of knockdown of α-synuclein on SCI but also helps to guide the treatment strategy for SCI.