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The light-activated TRP channel: the founding member of the TRP channel superfamily. 光激活TRP通道:TRP通道超家族的创始成员。
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2022-03-01 DOI: 10.1080/01677063.2022.2121824
Baruch Minke, William L Pak

The Drosophila light-activated Transient Receptor Potential (TRP) channel is the founding member of a large and diverse family of channel proteins. The Drosophila TRP (dTRP) channel, which generates the electrical response to light has been investigated in a great detail two decades before the first mammalian TRP channel was discovered. Thus, dTRP is unique among members of the TRP channel superfamily because its physiological role and the enzymatic cascade underlying its activation are established. In this article we outline the research leading to elucidation of dTRP as the light activated channel and focus on a major physiological property of the dTRP channel, which is indirect activation via a cascade of enzymatic reactions. These detailed pioneering studies, based on the genetic dissection approach, revealed that light activation of the Drosophila TRP channel is mediated by G-Protein-Coupled Receptor (GPCR)-dependent enzymatic cascade, in which phospholipase C β (PLC) is a crucial component. This physiological mechanism of Drosophila TRP channel activation was later found in mammalian TRPC channels. However, the initial studies on the mammalian TRPV1 channel indicated that it is activated directly by capsaicin, low pH and hot temperature (>42 °C). This mechanism of activation was apparently at odds with the activation mechanism of the TRPC channels in general and the Drosophila light activated TRP/TRPL channels in particular, which are target of a GPCR-activated PLC cascade. Subsequent studies have indicated that under physiological conditions TRPV1 is also target of a GPCR-activated PLC cascade in the generation of inflammatory pain. The Drosophila light-activated TRP channel is still a useful experimental paradigm because its physiological function as the light-activated channel is known, powerful genetic techniques can be applied to its further analysis, and signaling molecules involved in the activation of these channels are available.

果蝇光激活瞬时受体电位(TRP)通道是一个庞大而多样的通道蛋白家族的创始成员。果蝇TRP (dTRP)通道产生对光的电反应,早在第一个哺乳动物TRP通道被发现的20年前,人们就对其进行了详细的研究。因此,在TRP通道超家族的成员中,dTRP是独一无二的,因为它的生理作用和激活它的酶级联是确定的。在本文中,我们概述了导致阐明dTRP作为光激活通道的研究,并重点介绍了dTRP通道的一个主要生理特性,即通过一系列酶促反应间接激活。这些详细的开创性研究,基于遗传解剖方法,揭示了果蝇TRP通道的光激活是由g蛋白偶联受体(GPCR)依赖性酶级联介导的,其中磷脂酶C β (PLC)是一个关键组成部分。果蝇TRP通道激活的这种生理机制后来在哺乳动物TRPC通道中被发现。然而,对哺乳动物TRPV1通道的初步研究表明,它直接被辣椒素、低pH和高温(>42°C)激活。这种激活机制显然与一般的TRPC通道的激活机制不一致,特别是果蝇光激活的TRP/TRPL通道,它们是gpcr激活的PLC级联的目标。随后的研究表明,在生理条件下,TRPV1也是gpcr激活的PLC级联反应产生炎性疼痛的靶标。果蝇光激活TRP通道仍然是一个有用的实验范例,因为它作为光激活通道的生理功能是已知的,强大的遗传技术可以应用于其进一步分析,并且参与这些通道激活的信号分子是可用的。
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引用次数: 3
The force-from-lipid principle and its origin, a 'what is true for E. coli is true for the elephant' refrain. 脂质作用原理及其起源,“对大肠杆菌适用的道理对大象也适用”。
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2022-03-01 DOI: 10.1080/01677063.2022.2097674
Boris Martinac, Ching Kung

The force-from-lipid (FFL) principle states that it is the lateral stretch force from the lipid membrane that ultimately opens mechanosensitive (MS) channels, not the external tether nor the internal cytoskeleton. Piezo channels for certain touch or proprioception and the hair-cell channels for hearing or balance apparently obey this principle, which is based on the idea that the lipid bilayer is an amphipathic compartment with a distinct internal force-distribution profile. Physical stretch or insertion of chemical impurities alters this profile, driving channel shape change to conform to the new environment. Thus, FFL governs all dynamic proteins embedded in membrane, including Kv's and TRPs. This article retraces the humble origin of the FFL concept. Paramecium research first created the mind set and the resources to electrically explore other microbial membranes. Patch clamp revealed MS-channel activities from yeast and E. coli spheroplasts. Despite formidable obstacles against interdisciplinary research, the E. coli MS-channel protein, MscL, was purified through fractionation by following its activity, much like enzyme purification. Reconstituted into a simple lipid bilayer, pure MscL retains mechanosensitivity, thus firmly establishing the FFL principle in 1994. The relatively simple MscL and its functional cousin MscS soon became ideal models for detailed analyses. Like the DNA-RNA-protein 'central dogma' or ATP synthesis, FFL is a fundamental principle, which appeared early in evolution, retained in all cellular life forms, and is expected to contribute to future molecular research on sensations, homeostasis, and embryonic development.

脂质力(FFL)原理指出,最终打开机械敏感(MS)通道的是来自脂质膜的侧向拉伸力,而不是外部系索或内部细胞骨架。用于某些触觉或本体感觉的压电通道和用于听力或平衡的毛细胞通道显然遵循这一原则,这一原则是基于脂质双分子层是具有独特内力分布特征的两亲性隔室的观点。物理拉伸或化学杂质的插入改变了这种轮廓,驱动通道形状改变以适应新的环境。因此,FFL控制着嵌入膜中的所有动态蛋白,包括Kv和TRPs。本文回顾了FFL概念的卑微起源。草履虫的研究首先创造了用电探索其他微生物膜的思维模式和资源。膜片钳显示酵母和大肠杆菌球质体的ms通道活性。尽管跨学科研究存在巨大障碍,但大肠杆菌ms通道蛋白(MscL)通过跟踪其活性的分离纯化,就像酶纯化一样。纯MscL重组为简单的脂质双分子层,保留了机械敏感性,从而在1994年确立了FFL原理。相对简单的间充质干细胞及其功能性的同类间充质干细胞很快成为详细分析的理想模型。就像dna - rna -蛋白质的“中心法则”或ATP合成一样,FFL是一个基本原理,出现在进化的早期,保留在所有细胞生命形式中,并有望为未来的感觉、体内平衡和胚胎发育的分子研究做出贡献。
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引用次数: 8
Abnormal larval neuromuscular junction morphology and physiology in Drosophila prickle isoform mutants with known axonal transport defects and adult seizure behavior. 棘果蝇异型突变体的异常幼体神经肌肉连接形态和生理,已知轴突运输缺陷和成年癫痫行为。
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2022-03-01 DOI: 10.1080/01677063.2022.2093353
Atsushi Ueda, Tristan C D G O'Harrow, Xiaomin Xing, Salleh Ehaideb, J Robert Manak, Chun-Fang Wu

Previous studies have demonstrated the striking mutational effects of the Drosophila planar cell polarity gene prickle (pk) on larval motor axon microtubule-mediated vesicular transport and on adult epileptic behavior associated with neuronal circuit hyperexcitability. Mutant alleles of the prickle-prickle (pkpk) and prickle-spiny-legs (pksple) isoforms (hereafter referred to as pk and sple alleles, respectively) exhibit differential phenotypes. While both pk and sple affect larval motor axon transport, only sple confers motor circuit and behavior hyperexcitability. However, mutations in the two isoforms apparently counteract to ameliorate adult motor circuit and behavioral hyperexcitability in heteroallelic pkpk/pksple flies. We have further investigated the consequences of altered axonal transport in the development and function of the larval neuromuscular junction (NMJ). We uncovered robust dominant phenotypes in both pk and sple alleles, including synaptic terminal overgrowth (as revealed by anti-HRP and -Dlg immunostaining) and poor vesicle release synchronicity (as indicated by synaptic bouton focal recording). However, we observed recessive alteration of synaptic transmission only in pk/pk larvae, i.e. increased excitatory junctional potential (EJP) amplitude in pk/pk but not in pk/+ or sple/sple. Interestingly, for motor terminal excitability sustained by presynaptic Ca2+ channels, both pk and sple exerted strong effects to produce prolonged depolarization. Notably, only sple acted dominantly whereas pk/+ appeared normal, but was able to suppress the sple phenotypes, i.e. pk/sple appeared normal. Our observations contrast the differential roles of the pk and sple isoforms and highlight their distinct, variable phenotypic expression in the various structural and functional aspects of the larval NMJ.

先前的研究表明,果蝇平面细胞极性基因prickle (pk)对幼虫运动轴突微管介导的囊泡运输和与神经元回路高兴奋性相关的成人癫痫行为具有显著的突变作用。刺-刺(pkpk)和刺-刺-腿(pksple)同型突变等位基因(以下分别称为pk和单等位基因)表现出不同的表型。虽然pk和simple都影响幼虫的运动轴突运输,但只有simple会导致运动回路和行为亢奋。然而,在异等位基因pkpk/ pkple果蝇中,两种同工异构体的突变明显抵消了成年运动回路和行为过度兴奋性的改善。我们进一步研究了轴突运输改变对幼虫神经肌肉连接(NMJ)发育和功能的影响。我们发现pk等位基因和单一等位基因都存在强大的显性表型,包括突触末端过度生长(通过抗hrp和-Dlg免疫染色显示)和囊泡释放同步性差(通过突触扣点记录显示)。然而,我们仅在pk/pk幼虫中观察到突触传递的隐性改变,即pk/pk中兴奋性连接电位(EJP)振幅增加,而pk/+或单/单中没有。有趣的是,对于由突触前Ca2+通道维持的运动终端兴奋性,pk和simple都发挥了强大的作用,产生了延长的去极化。值得注意的是,只有sple起主导作用,而pk/+表现正常,但能够抑制sple表型,即pk/sple表现正常。我们的观察对比了pk和简单同种异构体的不同作用,并强调了它们在幼虫NMJ的各种结构和功能方面的不同,可变的表型表达。
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引用次数: 0
Abnormalities of neural stem cells in Lesch-Nyhan disease. 莱希-尼汉病的神经干细胞异常。
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2022-03-01 Epub Date: 2022-10-13 DOI: 10.1080/01677063.2022.2129632
Ashok R Dinasarapu, Diane J Sutcliffe, Fatemeh Seifar, Jasper E Visser, H A Jinnah

Lesch-Nyhan disease (LND) is a neurodevelopmental disorder caused by variants in the HPRT1 gene, which encodes the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGprt). HGprt deficiency provokes numerous metabolic changes which vary among different cell types, making it unclear which changes are most relevant for abnormal neural development. To begin to elucidate the consequences of HGprt deficiency for developing human neurons, neural stem cells (NSCs) were prepared from 6 induced pluripotent stem cell (iPSC) lines from individuals with LND and compared to 6 normal healthy controls. For all 12 lines, gene expression profiles were determined by RNA-seq and protein expression profiles were determined by shotgun proteomics. The LND lines revealed significant changes in expression of multiple genes and proteins. There was little overlap in findings between iPSCs and NSCs, confirming the impact of HGprt deficiency depends on cell type. For NSCs, gene expression studies pointed towards abnormalities in WNT signaling, which is known to play a role in neural development. Protein expression studies pointed to abnormalities in the mitochondrial F0F1 ATPase, which plays a role in maintaining cellular energy. These studies point to some mechanisms that may be responsible for abnormal neural development in LND.

莱希-尼汉病(LND)是一种由编码次黄嘌呤鸟嘌呤磷酸核糖转移酶(HGprt)的HPRT1基因变异引起的神经发育障碍。HGprt缺乏会引发许多不同细胞类型的代谢变化,因此尚不清楚哪些变化与异常神经发育最相关。为了开始阐明HGprt缺乏对发育中的人类神经元的影响,从患有LND的个体的6个诱导多能干细胞(iPSC)系制备神经干细胞(NSCs),并与6个正常健康对照进行比较。对于所有12个品系,通过RNA-seq测定基因表达谱,通过鸟枪蛋白质组学测定蛋白质表达谱。LND系揭示了多种基因和蛋白质表达的显著变化。iPSC和NSCs之间的发现几乎没有重叠,证实HGprt缺乏的影响取决于细胞类型。对于神经干细胞,基因表达研究指出WNT信号异常,已知WNT信号在神经发育中发挥作用。蛋白质表达研究指出线粒体F0F1-ATP酶异常,该酶在维持细胞能量方面发挥作用。这些研究指出了一些可能导致LND神经发育异常的机制。
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引用次数: 0
The origins of the force-from-lipid principle and the founding member of the TRP channel superfamily. 脂质力原理的起源和TRP通道超家族的创始成员。
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2022-03-01 DOI: 10.1080/01677063.2022.2132104
Chun-Fang Wu
The 2021 Nobel Prize in Medicine and Physiology recognized the seminal work of David Julius, who established the temperature and pain sensory mechanisms based on the TRPV channel, and Ardem Patapoutian, who resolved the stretch activation mechanism for touch and proprietary sensation via Piezo channels. We are fortunate and proud to publish a special section on the force-from-lipid principle underlining Piezo channel activation and the origin of the first TRP channel, prepared by the pioneers who initiated the early work that led to the discoveries (Martinac & Kung, 2022; Minke & Pak, 2022). Professors Baruch Minke and William Pak recount the story of their early endeavor to reveal the phototransduction process mediated by the TRP channel in the fruit fly Drosophila. This light-sensitive TRP channel is now recognized as the founding member of the TRP channel superfamily, which encompasses a large category of channels underpinning different sensory mechanisms, including visual, auditory, thermal, and mechanosensory transduction. The functioning of Piezo channels turns out to be based on the same force-from-lipid principle, originating from lipid membrane lateral force without involving any cytoskeletal or cell adhesion molecules. As professors Ching Kung and Boris Martinac recount in their article, the initial finding actually originated from studies on a special strain of giant E. coli. Indeed, ‘what is true for E. coli is true for the elephant’.
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引用次数: 0
lncRNA XIST induces Aβ accumulation and neuroinflammation by the epigenetic repression of NEP in Alzheimer's disease. lncRNA XIST通过NEP在阿尔茨海默病中的表观遗传抑制诱导Aβ积累和神经炎症。
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2022-03-01 Epub Date: 2022-01-31 DOI: 10.1080/01677063.2022.2028784
Xi-Wu Yan, Huai-Jun Liu, Yu-Xing Hong, Ting Meng, Jun Du, Cheng Chang

Alzheimer's disease (AD) is the leading cause of dementia globally, but effective treatment is lacking. We aimed to explore lncRNA XIST role in AD and the mechanisms involved in the effect of changes in lncRNA XIST on the expression of Aβ-degrading enzymes. The mouse model of AD and the cell model induced by Aβ were established. LncRNA XIST, IDE, NEP, Plasmin, ACE, EZH2 expressions and distribution of XIST in the nucleus and cytoplasm were detected by qRT-PCR. Inflammatory cytokines IL-6, IL-1β, TNFα, IL-8, and Aβ42 levels were detected by ELISA. TUNEL was used to measure brain tissue damage. Cell proliferation was detected by CCK-8 assay. Flow cytometry detected cell apoptosis. RIP validated the combination of XIST and EZH2. ChIP verified that XIST recruits EZH2 to mediate enrichment of HEK27me3 in the NEP promoter region. The protein expression in brain tissues and cells was detected by Western blot. The expression of lncRNA XIST was increased in AD mice and cell models. Inflammation and injury of nerve cells occurred in AD mice and cell models. The knockdown of lncRNA XIST alleviated Aβ-induced neuronal inflammation and damage. LncRNA XIST affected the expression of Aβ-degrading enzyme NEP, and lncRNA XIST was negatively correlated with NEP expression in AD mice. LncRNA XIST regulated NEP expression partly through epigenetic regulation by binding with EZH2. LncRNA XIST mediated neuronal inflammation and injury through epigenetic regulation of NEP. Overall, our study found that lncRNA XIST induced Aβ accumulation and neuroinflammation by the epigenetic repression of NEP in AD.

阿尔茨海默病(AD)是全球痴呆症的主要原因,但缺乏有效的治疗方法。我们旨在探讨lncRNA XIST在AD中的作用,以及lncRNA XIST改变对a β-降解酶表达影响的机制。建立小鼠AD模型和Aβ诱导的细胞模型。采用qRT-PCR检测LncRNA XIST、IDE、NEP、Plasmin、ACE、EZH2在细胞核和细胞质中的表达和分布。ELISA法检测各组炎症因子IL-6、IL-1β、TNFα、IL-8、a - β42水平。TUNEL用于测量脑组织损伤。CCK-8法检测细胞增殖。流式细胞术检测细胞凋亡。RIP验证了XIST和EZH2的结合。ChIP证实XIST招募EZH2介导NEP启动子区域HEK27me3的富集。Western blot检测脑组织及细胞蛋白表达。lncRNA XIST在AD小鼠和细胞模型中表达升高。AD小鼠和细胞模型均出现神经细胞炎症和损伤。lncRNA XIST的下调可减轻a β诱导的神经元炎症和损伤。LncRNA XIST影响a β-降解酶NEP的表达,且LncRNA XIST与AD小鼠NEP表达呈负相关。LncRNA XIST部分通过与EZH2结合的表观遗传调控调控NEP的表达。LncRNA XIST通过NEP的表观遗传调控介导神经元炎症和损伤。总的来说,我们的研究发现lncRNA XIST通过表观遗传抑制NEP在AD中诱导Aβ积累和神经炎症。
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引用次数: 14
Reduction of the α-synuclein expression promotes slowing down early neuropathology development in the Drosophila model of Parkinson’s disease α-突触核蛋白表达的降低促进帕金森病果蝇模型早期神经病理发展的减缓
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2022-01-02 DOI: 10.1080/01677063.2022.2064462
Ilia M Golomidov, Evgenia M. Latypova, E. Ryabova, O. Bolshakova, A. Komissarov, S. Sarantseva
Abstract Parkinson’s disease (PD) is a neurodegenerative disease characterised by the formation of Lewy bodies and progressive loss of dopaminergic (DA) neurons in the substantia nigra. Lewy bodies mainly consist of α-synuclein, which plays a critical role in the pathophysiology of PD. The α-synuclein is encoded by the SNCA gene and is the first identified gene associated with hereditary PD. Currently, there are at least six disease-associated mutations in α-synuclein that cause dominantly inherited familial forms of PD. Targeted expression of human SNCA.WT/SNCA.A30P/SNCA.A53T gene in Drosophila melanogaster over specific times employing a temperature-dependent UAS/GAL4 – GAL80 system allows for the evaluation of neurodegenerative processes. In this study, SNCA was expressed only in the adult stage of Drosophila development for 1 or 2 weeks, followed by repression of gene expression for the rest of the fly’s life. It was demonstrated that the level of pathology significantly depends on the duration of α-synuclein expression. SNCA gene expression over a longer period of time caused the death of DA neurons, decreased levels of dopamine and locomotor ability. In this case, the observed neurodegenerative processes correlated with the accumulation of α-synuclein in the Drosophila brain. Importantly, repression of α-synuclein expression led to elimination of the soluble protein fraction, in contrast to the insoluble fraction. No further significant development of characteristic signs of pathology was observed after the α-synuclein expression was blocked. Thus, we suggest that reduction of α-synuclein expression alone contributes to slowing down the development of PD-like symptoms.
摘要帕金森病(PD)是一种神经退行性疾病,其特征是黑质中路易体的形成和多巴胺能(DA)神经元的逐渐丧失。路易体主要由α-突触核蛋白组成,在帕金森病的病理生理学中起着至关重要的作用。使用温度依赖性UAS/GAL4–GAL80系统在特定时间内在黑腹果蝇中靶向表达人SNCA.WT/SNCA.A30P/SNCA.A53T基因,可以评估神经退行性过程。在这项研究中,SNCA仅在果蝇发育的成年阶段表达1或2 数周,然后在苍蝇的余生中抑制基因表达。研究表明,病理水平显著依赖于α-突触核蛋白表达的持续时间。SNCA基因长时间表达导致DA神经元死亡,多巴胺水平下降,运动能力下降。在这种情况下,观察到的神经退行性过程与果蝇大脑中α-突触核蛋白的积累有关。重要的是,α-突触核蛋白表达的抑制导致可溶性蛋白部分的消除,而不溶性部分则相反。α-突触核蛋白表达被阻断后,没有观察到病理学特征性体征的进一步显著发展。因此,我们认为,α-突触核蛋白表达的减少单独有助于减缓PD样症状的发展。
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引用次数: 0
LncRNA GAS5 promotes epilepsy progression through the epigenetic repression of miR-219, in turn affecting CaMKIIγ/NMDAR pathway LncRNA GAS5通过miR-219的表观遗传学抑制促进癫痫进展,进而影响CaMKIIγ/NDAR通路
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2022-01-02 DOI: 10.1080/01677063.2022.2067536
Chen-sheng Zhao, Dong-xing Liu, Yanping Fan, Jian-kun Wu
Abstract It has been widely reported that dysregulated long-chain noncoding RNAs (lncRNAs) are closely associated with epilepsy. This study aimed to probe the function of lncRNA growth arrest-specific 5 (GAS5), microRNA (miR)-219 and Calmodulin-dependent protein kinase II (CaMKII)γ/N-methyl-D-aspartate receptor (NMDAR) pathway in epilepsy. Epileptic cell and animal models were constructed using magnesium deficiency treatment and diazepam injection, respectively. GAS5 and miR-219 expressions in epileptic cell and animal models were determined using qRT-PCR assay. The protein levels of CaMKIIγ, NMDAR and apoptosis-related proteins levels were assessed by western blot. Cell counting kit-8 (CCK-8) assay was employed to determine cell proliferation. Besides, TNFα, IL-1β, IL-6 and IL-8 levels were analyzed using enzyme-linked immunosorbent assay (ELISA). Furthermore, cell apoptosis was evaluated using TUNEL staining and flow cytometric analysis. Finally, the binding relationship between GAS5 and EZH2 was verified using RIP and ChIP assay. Our results revealed that GAS5 was markedly upregulated in epileptic cell and animal models, while miR-219 was down-regulated. GAS5 knockdown dramatically increased cell proliferation of epileptic cells, whereas suppressed inflammation and the apoptosis. Furthermore, our results showed that GAS5 epigenetically suppressed transcriptional miR-219 expression via binding to EZH2. miR-219 mimics significantly enhanced cell proliferation of epileptic cells, while inhibited inflammation and the apoptosis, which was neutralized by CaMKIIγ overexpression. Finally, miR-219 inhibition reversed the effects of GAS5 silence on epileptic cells, which was eliminated by CaMKIIγ inhibition. In conclusion, GAS5 affected inflammatory response and cell apoptosis of epilepsy via inhibiting miR-219 and further regulating CaMKIIγ/NMDAR pathway (See graphic summary in Supplementary Material).
摘要广泛报道,失调的长链非编码RNA(lncRNA)与癫痫密切相关。本研究旨在探讨lncRNA生长停滞特异性5(GAS5)、微小RNA(miR)-219和钙调蛋白依赖性蛋白激酶II(CaMKII)γ/N-甲基-D-天冬氨酸受体(NMDAR)通路在癫痫中的作用。分别使用镁缺乏治疗和安定注射液构建癫痫细胞和动物模型。使用qRT-PCR测定癫痫细胞和动物模型中GAS5和miR-219的表达。免疫印迹法检测CaMKIIγ、NMDAR蛋白水平及细胞凋亡相关蛋白水平。细胞计数试剂盒-8(CCK-8)测定法用于测定细胞增殖。采用酶联免疫吸附试验(ELISA)测定TNFα、IL-1β、IL-6和IL-8水平。此外,使用TUNEL染色和流式细胞术分析来评估细胞凋亡。最后,使用RIP和ChIP分析验证了GAS5和EZH2之间的结合关系。我们的研究结果显示,GAS5在癫痫细胞和动物模型中显著上调,而miR-219则下调。GAS5基因敲除显著增加癫痫细胞的增殖,同时抑制炎症和细胞凋亡。此外,我们的研究结果表明,GAS5通过与EZH2结合,表观遗传学抑制转录miR-219的表达。miR-219模拟显著增强癫痫细胞的细胞增殖,同时抑制炎症和细胞凋亡,这被CaMKIIγ过表达所中和。最后,miR-219的抑制逆转了GAS5沉默对癫痫细胞的影响,这种影响被CaMKIIγ的抑制所消除。总之,GAS5通过抑制miR-219和进一步调节CaMKIIγ/NDAR途径影响癫痫的炎症反应和细胞凋亡(见补充材料中的图形摘要)。
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引用次数: 4
Novel insights into the genetic profile of hereditary spastic paraplegia in India 新见解遗传痉挛性截瘫在印度的遗传概况
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2022-01-02 DOI: 10.1080/01677063.2022.2064463
Sundarapandian Narendiran, M. Debnath, S. Shivaram, Ramakrishnan Kannan, Shivani Sharma, R. Christopher, D. Seshagiri, S. Jain, M. Purushottam, Sandhya Mangalore, R. Bharath, P. Bindu, S. Sinha, A. Taly, M. Nagappa
Abstract The Hereditary Spastic Paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders characterized by length dependent degeneration of the corticospinal tracts. Genetic data related to HSPs are limited from India. We aimed to comprehensively analyse the phenotypic characteristics and genetic basis of a large cohort of HSP from India. Patients with HSP phenotype were evaluated for their clinical features, electrophysiological and radiological abnormalities. Genetic analyses were carried out by clinical exome sequencing (n = 52) and targeted sequencing (n = 5). The cohort comprised of 57 probands (M:F 40:17, age: 3.5–49 years). Based on the phenotype, the cohort could be categorized as ‘pure’ (n = 15, 26.3%) and ‘complicated’ (n = 42, 73.7%) HSP. Brain MRI showed thin corpus callosum (n = 10), periventricular hyperintensities (n = 20), cerebral atrophy (n = 3), cerebellar atrophy (n = 3) and diffuse atrophy (n = 4). Sixty-seven variants representing 40 genes were identified including 47 novel variants. Forty-eight patients (84.2%) had variants in genes previously implicated in HSP and other spastic paraplegia syndromes (SPG genes = 24, non-SPG genes = 24); among these 13 had variations in more than one gene and 12 patients (21.0%) had variations in genes implicated in potentially treatable/modifiable metabolic disorders (MTHFR = 8, MTRR = 1, ARG1 = 2 and ABCD1 = 1). In nine patients, no genetic variants implicated in spastic paraplegia phenotype were identified. Thus, the present study from India highlights the phenotypic complexities and spectrum of genetic variations in patients with HSP including those implicated in metabolically modifiable disorders. It sets a platform for carrying out functional studies to validate the causal role of the novel variants and variants of uncertain significance.
遗传性痉挛性截瘫(HSPs)是一组临床和遗传异质性疾病,其特征是皮质脊髓束的长度依赖性变性。印度与热休克蛋白相关的遗传数据有限。我们的目的是全面分析来自印度的一个大队列热休克综合征的表型特征和遗传基础。对HSP表型患者的临床特征、电生理和放射学异常进行评估。通过临床外显子组测序(n = 52)和靶向测序(n = 5)进行遗传分析。该队列由57个先证者组成(男:女40:17,年龄:3.5-49岁)。根据表型,该队列可分为“纯”(n = 15, 26.3%)和“复杂”(n = 42, 73.7%) HSP。脑MRI表现为胼胝体薄(10例),脑室周围高信号(20例),脑萎缩(3例),小脑萎缩(3例),弥漫性萎缩(4例)。共鉴定出40个基因的67个变异,其中包括47个新变异。48例患者(84.2%)具有先前与HSP和其他痉挛性截瘫综合征相关的基因变异(SPG基因= 24,非SPG基因= 24);在这些患者中,13名患者有一个以上的基因变异,12名患者(21.0%)有与潜在可治疗/可改变代谢疾病相关的基因变异(MTHFR = 8, MTRR = 1, ARG1 = 2和ABCD1 = 1)。在9例患者中,没有发现与痉挛性截瘫表型相关的遗传变异。因此,目前来自印度的研究强调了HSP患者的表型复杂性和遗传变异谱,包括那些与代谢可改变疾病有关的患者。它为开展功能研究提供了一个平台,以验证新变体和不确定意义变体的因果作用。
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引用次数: 1
Fly seizure EEG: field potential activity in the Drosophila brain. 苍蝇发作脑电图:果蝇大脑的场电位活动。
IF 1.9 4区 医学 Q3 GENETICS & HEREDITY Pub Date : 2021-09-01 DOI: 10.1080/01677063.2021.1950714
Atulya Iyengar, Chun-Fang Wu

Hypersynchronous neural activity is a characteristic feature of seizures. Although many Drosophila mutants of epilepsy-related genes display clear behavioral spasms and motor unit hyperexcitability, field potential measurements of aberrant hypersynchronous activity across brain regions during seizures have yet to be described. Here, we report a straightforward method to observe local field potentials (LFPs) from the Drosophila brain to monitor ensemble neural activity during seizures in behaving tethered flies. High frequency stimulation across the brain reliably triggers a stereotypic sequence of electroconvulsive seizure (ECS) spike discharges readily detectable in the dorsal longitudinal muscle (DLM) and coupled with behavioral spasms. During seizure episodes, the LFP signal displayed characteristic large-amplitude oscillations with a stereotypic temporal correlation to DLM flight muscle spiking. ECS-related LFP events were clearly distinct from rest- and flight-associated LFP patterns. We further characterized the LFP activity during different types of seizures originating from genetic and pharmacological manipulations. In the 'bang-sensitive' sodium channel mutant bangsenseless (bss), the LFP pattern was prolonged, and the temporal correlation between LFP oscillations and DLM discharges was altered. Following administration of the pro-convulsant GABAA blocker picrotoxin, we uncovered a qualitatively different LFP activity pattern, which consisted of a slow (1-Hz), repetitive, waveform, closely coupled with DLM bursting and behavioral spasms. Our approach to record brain LFPs presents an initial framework for electrophysiological analysis of the complex brain-wide activity patterns in the large collection of Drosophila excitability mutants.

超同步神经活动是癫痫发作的一个特征。尽管许多癫痫相关基因的果蝇突变体表现出明显的行为痉挛和运动单位过度兴奋性,但癫痫发作期间大脑区域异常超同步活动的场电位测量尚未得到描述。在这里,我们报告了一种直接观察果蝇大脑局部场电位(LFPs)的方法,以监测行为系缚果蝇癫痫发作期间的整体神经活动。通过大脑的高频刺激可触发电惊厥发作(ECS)脉冲放电的刻板序列,这在背纵肌(DLM)中很容易检测到,并伴有行为痉挛。在癫痫发作期间,LFP信号表现出特征性的大振幅振荡,与DLM飞行肌尖峰具有典型的时间相关性。ecs相关的LFP事件明显不同于休息和飞行相关的LFP模式。我们进一步表征了LFP在不同类型的癫痫发作中由遗传和药理学操作引起的活性。在“bang-sensitive”钠通道突变体(bss)中,LFP模式被延长,LFP振荡与DLM放电之间的时间相关性被改变。在给予促惊厥GABAA阻滞剂微毒素后,我们发现LFP活性模式在质量上有所不同,该模式由缓慢(1 hz),重复的波形组成,与DLM破裂和行为痉挛密切相关。我们记录大脑lfp的方法为大量果蝇兴奋性突变体中复杂的全脑活动模式的电生理分析提供了一个初始框架。
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引用次数: 0
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Journal of neurogenetics
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