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Genetic and pharmacologic alterations of claudin9 levels suffice to induce functional and mature inner hair cells. claudin9水平的遗传和药理学改变足以诱导功能性和成熟的内毛细胞。
Pub Date : 2024-11-08 DOI: 10.1101/2023.10.08.561387
Yingying Chen, Jeong Han Lee, Jin Li, Seojin Park, Maria C Perez Flores, Braulio Peguero, Jennifer Kersigo, Mincheol Kang, Jinsil Choi, Lauren Levine, Michael Anne Gratton, Bernd Fritzsch, Ebenezer N Yamoah

Hearing loss is the most common form of sensory deficit. It occurs predominantly due to hair cell (HC) loss. Mammalian HCs are terminally differentiated by birth, making HC loss challenging to replace. Here, we show the pharmacogenetic downregulation of Cldn9, a tight junction protein, generates robust supernumerary inner HCs (IHCs) in mice. The ectopic IHC shared functional and synaptic features akin to typical IHCs and were surprisingly and remarkably preserved for at least fifteen months >50% of the mouse's life cycle. In vivo, Cldn9 knockdown using shRNA on postnatal days (P) P2-7 yielded analogous functional ectopic IHCs that were equally durably conserved. The findings suggest that Cldn9 levels coordinate embryonic and postnatal HC differentiation, making it a viable target for altering IHC development pre- and post-terminal differentiation.

听力损失是最常见的感觉缺陷形式。它主要是由于毛细胞(HC)的损失而发生的。哺乳动物HC在出生时就已分化到晚期,因此HC的丧失是无法治愈的。在这里,我们展示了紧密连接蛋白Cldn9的药物遗传学下调,在小鼠中产生强大的多个内部HC(IHCs)。假定的异位IHCs具有类似于典型IHCs的功能和突触特征,并且令人惊讶地显著保存了至少15个月>小鼠生命周期的50%。在体内,在出生后第(P)P1-7天使用shRNA敲除Cldn9产生了类似的功能性推定异位IHCs,这些IHCs同样持久保守。研究结果表明,Cldn9水平协调了胚胎和出生后HC的分化,使其成为改变IHC分化前后发育的可行靶点。
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引用次数: 0
Classification of psychedelics and psychoactive drugs based on brain-wide imaging of cellular c-Fos expression. 根据细胞 c-Fos 表达的全脑成像对迷幻药进行分类。
Pub Date : 2024-11-07 DOI: 10.1101/2024.05.23.590306
Farid Aboharb, Pasha A Davoudian, Ling-Xiao Shao, Clara Liao, Gillian N Rzepka, Cassandra Wojtasiewicz, Mark Dibbs, Jocelyne Rondeau, Alexander M Sherwood, Alfred P Kaye, Alex C Kwan

Psilocybin, ketamine, and MDMA are psychoactive compounds that exert behavioral effects with distinguishable but also overlapping features. The growing interest in using these compounds as therapeutics necessitates preclinical assays that can accurately screen psychedelics and related analogs. We posit that a promising approach may be to measure drug action on markers of neural plasticity in native brain tissues. We therefore developed a pipeline for drug classification using light sheet fluorescence microscopy of immediate early gene expression at cellular resolution followed by machine learning. We tested male and female mice with a panel of drugs, including psilocybin, ketamine, 5-MeO-DMT, 6-fluoro-DET, MDMA, acute fluoxetine, chronic fluoxetine, and vehicle. In one-versus-rest classification, the exact drug was identified with 67% accuracy, significantly above the chance level of 12.5%. In one-versus-one classifications, psilocybin was discriminated from 5-MeO-DMT, ketamine, MDMA, or acute fluoxetine with >95% accuracy. We used Shapley additive explanation to pinpoint the brain regions driving the machine learning predictions. Our results support a novel approach for characterizing and validating psychoactive drugs with psychedelic properties.

迷幻药、氯胺酮和亚甲二氧基甲基苯丙胺都是具有精神活性的化合物,它们产生的行为效应既有区别又有重叠。将这些化合物用作治疗药物的兴趣与日俱增,因此需要能准确筛选迷幻剂和相关类似物的临床前试验。我们认为,衡量药物对原生脑组织中神经可塑性标志物的作用可能是一种很有前途的方法。因此,我们利用光片荧光显微镜对细胞分辨率的即刻早期基因表达进行了分析,然后利用机器学习技术开发了一种药物分类方法。我们用一系列药物对雄性和雌性小鼠进行了测试,包括迷幻药、氯胺酮、5-MeO-DMT、6-氟-DET、摇头丸、急性氟西汀、慢性氟西汀和车辆。在单对单分类中,准确识别药物的准确率为 66%,大大高于 12.5% 的概率水平。在单对单分类中,将迷幻药与 5-MeO-DMT、氯胺酮、摇头丸或急性氟西汀区分开来的准确率大于 95%。我们使用沙普利加法解释来确定驱动机器学习预测的大脑区域。我们的研究结果为筛选具有迷幻特性的精神活性药物提供了一种新方法。
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引用次数: 0
moPepGen: Rapid and Comprehensive Identification of Non-canonical Peptides. moPepGen:快速、全面的蛋白质形式鉴定。
Pub Date : 2024-11-05 DOI: 10.1101/2024.03.28.587261
Chenghao Zhu, Lydia Y Liu, Annie Ha, Takafumi N Yamaguchi, Helen Zhu, Rupert Hugh-White, Julie Livingstone, Yash Patel, Thomas Kislinger, Paul C Boutros

Gene expression is a multi-step transformation of biological information from its storage form (DNA) into functional forms (protein and some RNAs). Regulatory activities at each step of this transformation multiply a single gene into a myriad of proteoforms. Proteogenomics is the study of how genomic and transcriptomic variation creates this proteomic diversity, and is limited by the challenges of modeling the complexities of gene-expression. We therefore created moPepGen, a graph-based algorithm that comprehensively generates non-canonical peptides in linear time. moPepGen works with multiple technologies, in multiple species and on all types of genetic and transcriptomic data. In human cancer proteomes, it enumerates previously unobservable noncanonical peptides arising from germline and somatic genomic variants, noncoding open reading frames, RNA fusions and RNA circularization. By enabling efficient detection and quantitation of previously hidden proteins in both existing and new proteomic data, moPepGen facilitates all proteogenomics applications. It is available at: https://github.com/uclahs-cds/package-moPepGen.

基因表达是生物信息从储存形式(DNA)到功能形式(蛋白质和某些 RNA)的多步骤转化。在这一转化过程中,每一步的调控活动都会将单个基因倍增为无数种蛋白形式。蛋白基因组学研究的是基因组和转录组的变异如何产生这种蛋白形式的多样性,它受到基因表达复杂性建模挑战的限制。因此,我们创建了moPepGen,这是一种基于图的算法,能在线性时间内全面枚举蛋白形式。moPepGen可与多种技术结合使用,适用于多个物种以及所有类型的基因和转录组数据。在人类癌症蛋白质组中,它能检测和量化因种系和体细胞基因组变异、非编码开放阅读框、RNA融合和RNA环化而产生的以前未观察到的非典型多肽。moPepGen 能在现有的和新的蛋白质组数据中有效地识别和定量以前隐藏的蛋白质,从而为所有蛋白质组学应用提供便利。请访问:https://github.com/uclahs-cds/package-moPepGen。
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引用次数: 0
DNA repair and anti-cancer mechanisms in the long-lived bowhead whale. 长寿弓头鲸的 DNA 修复和抗癌机制。
Pub Date : 2024-11-05 DOI: 10.1101/2023.05.07.539748
Denis Firsanov, Max Zacher, Xiao Tian, Todd L Sformo, Yang Zhao, Greg Tombline, J Yuyang Lu, Zhizhong Zheng, Luigi Perelli, Enrico Gurreri, Li Zhang, Jing Guo, Anatoly Korotkov, Valentin Volobaev, Seyed Ali Biashad, Zhihui Zhang, Johanna Heid, Alex Maslov, Shixiang Sun, Zhuoer Wu, Jonathan Gigas, Eric Hillpot, John Martinez, Minseon Lee, Alyssa Williams, Abbey Gilman, Nicholas Hamilton, Ena Haseljic, Avnee Patel, Maggie Straight, Nalani Miller, Julia Ablaeva, Lok Ming Tam, Chloé Couderc, Michael Hoopman, Robert Moritz, Shingo Fujii, Dan J Hayman, Hongrui Liu, Yuxuan Cai, Anthony K L Leung, Mirre J P Simons, Zhengdong Zhang, C Bradley Nelson, Lisa M Abegglen, Joshua D Schiffman, Vadim N Gladyshev, Mauro Modesti, Giannicola Genovese, Jan Vijg, Andrei Seluanov, Vera Gorbunova

At over 200 years, the maximum lifespan of the bowhead whale exceeds that of all other mammals. The bowhead is also the second-largest animal on Earth, reaching over 80,000 kg 1 . Despite its very large number of cells and long lifespan, the bowhead is not highly cancer-prone, an incongruity termed Peto's Paradox 2 . This phenomenon has been explained by the evolution of additional tumor suppressor genes in other larger animals, supported by research on elephants demonstrating expansion of the p53 gene 3-5 . Here we show that bowhead whale fibroblasts undergo oncogenic transformation after disruption of fewer tumor suppressors than required for human fibroblasts. However, analysis of DNA repair revealed that bowhead cells repair double strand breaks (DSBs) and mismatches with uniquely high efficiency and accuracy compared to other mammals. The protein CIRBP, implicated in protection from genotoxic stress, was present in very high abundance in the bowhead whale relative to other mammals. We show that CIRBP and its downstream protein RPA2, also present at high levels in bowhead cells, increase the efficiency and fidelity of DNA repair in human cells. These results indicate that rather than possessing additional tumor suppressor genes as barriers to oncogenesis, the bowhead whale relies on more accurate and efficient DNA repair to preserve genome integrity. This strategy which does not eliminate damaged cells but repairs them may be critical for the long and cancer-free lifespan of the bowhead whale.

弓头鲸的最长寿命超过 200 年,超过了所有其他哺乳动物。弓头鲸也是地球上第二大动物,体重超过 8 万公斤1 。尽管弓头鲸的细胞数量非常多,寿命也很长,但它并不容易患癌症,这被称为 "佩托悖论"(Peto's Paradox)2 。这种现象的原因是其他大型动物进化出了更多的肿瘤抑制基因,对大象的研究也证明了 p53 基因的扩增 3-5 。在这里,我们发现弓头鲸的成纤维细胞在破坏了比人类成纤维细胞所需的更少的肿瘤抑制基因后发生了致癌转化。然而,对 DNA 修复的分析表明,与其他哺乳动物相比,弓头鲸细胞修复双链断裂(DSB)和错配的效率和准确性都很高。与其他哺乳动物相比,弓头鲸体内的蛋白质 CIRBP 的丰度非常高,而 CIRBP 与保护基因免受基因毒性应激有关。我们的研究表明,CIRBP 及其下游蛋白 RPA2(也在弓头鲸细胞中大量存在)提高了人类细胞 DNA 修复的效率和保真度。这些结果表明,与其说弓头鲸拥有额外的肿瘤抑制基因作为肿瘤发生的屏障,不如说它依靠更准确、更高效的 DNA 修复来保持基因组的完整性。这种不消除受损细胞,而是修复它们的策略,可能是弓头鲸寿命长、不患癌症的关键所在。
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引用次数: 0
Joint representation and visualization of derailed cell states with Decipher. 深度生成模型解读急性髓性白血病的脱轨轨迹。
Pub Date : 2024-11-05 DOI: 10.1101/2023.11.11.566719
Achille Nazaret, Joy Linyue Fan, Vincent-Philippe Lavallée, Cassandra Burdziak, Andrew E Cornish, Vaidotas Kiseliovas, Robert L Bowman, Ignas Masilionis, Jaeyoung Chun, Shira E Eisman, James Wang, Justin Hong, Lingting Shi, Ross L Levine, Linas Mazutis, David Blei, Dana Pe'er, Elham Azizi

Biological insights often depend on comparing conditions such as disease and health, yet we lack effective computational tools for integrating single-cell genomics data across conditions or characterizing transitions from normal to deviant cell states. Here, we present Decipher, a deep generative model that characterizes derailed cell-state trajectories. Decipher jointly models and visualizes gene expression and cell state from normal and perturbed single-cell RNA-seq data, revealing shared and disrupted dynamics. We demonstrate its superior performance across diverse contexts, including in pancreatitis with oncogene mutation, acute myeloid leukemia, and gastric cancer.

单细胞基因组学有可能以一种无偏倚的方式绘制细胞状态及其动态,以响应疾病等扰动。然而,阐明细胞状态从健康到疾病的转变需要分析来自扰动样本和未扰动参考样本的数据。现有的整合和联合可视化来自不同背景的单细胞数据集的方法往往会消除关键的生物学差异,或者不能正确地协调共享机制。我们提出了Decipher模型,该模型结合了变分自编码器和深度指数族来重建脱轨轨迹(https://github.com/azizilab/decipher)。破译联合代表正常和受干扰的单细胞RNA-seq数据集,揭示共享和破坏的动态。它进一步引入了一种新的方法来可视化数据,而不需要UMAP或TSNE等方法。我们在急性髓性白血病患者骨髓标本的数据上展示了Decipher,表明它成功地表征了与正常造血的差异,并识别了当每个患者获得NPM1驱动突变时被破坏的转录程序。
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引用次数: 0
Catalytic growth in a shared enzyme pool ensures robust control of centrosome size. 共享酶池中的催化生长确保了中心体大小的稳健控制。
Pub Date : 2024-11-04 DOI: 10.1101/2023.06.06.543875
Deb Sankar Banerjee, Shiladitya Banerjee

Accurate regulation of centrosome size is essential for ensuring error-free cell division, and dysregulation of centrosome size has been linked to various pathologies, including developmental defects and cancer. While a universally accepted model for centrosome size regulation is lacking, prior theoretical and experimental works suggest a centrosome growth model involving autocatalytic assembly of the pericentriolar material. Here we show that the autocatalytic assembly model fails to explain the attainment of equal centrosome sizes, which is crucial for error-free cell division. Incorporating latest experimental findings into the molecular mechanisms governing centrosome assembly, we introduce a new quantitative theory for centrosome growth involving catalytic assembly within a shared pool of enzymes. Our model successfully achieves robust size equality between maturing centrosome pairs, mirroring cooperative growth dynamics observed in experiments. To validate our theoretical predictions, we compare them with available experimental data and demonstrate the broad applicability of the catalytic growth model across different organisms, which exhibit distinct growth dynamics and size scaling characteristics.

中心体大小的精确调节对于确保无错误的细胞分裂至关重要,中心体尺寸的失调与各种病理有关,包括发育缺陷和癌症。虽然缺乏普遍接受的中心体尺寸调节模型,但先前的理论和实验工作表明,中心体生长模型涉及心周物质的自催化组装。在这里,我们表明,自催化组装模型无法解释中心体大小相等的实现,这对于无错误的细胞分裂至关重要。将最新的实验结果纳入控制中心体组装的分子机制中,我们引入了一种新的中心体生长的定量理论,该理论涉及在共享的酶池中的催化组装。我们的模型成功地实现了成熟中心体对之间稳健的大小相等,反映了实验中观察到的合作生长动力学。为了验证我们的理论预测,我们将其与现有的实验数据进行了比较,并证明了催化生长模型在不同生物体中的广泛适用性,这些生物体表现出不同的生长动力学和尺寸尺度特征。
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引用次数: 0
CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis. iPSC衍生神经元的CRISPR筛选揭示了tau蛋白稳定的原理。
Pub Date : 2024-11-04 DOI: 10.1101/2023.06.16.545386
Avi J Samelson, Nabeela Ariqat, Justin McKetney, Gita Rohanitazangi, Celeste Parra Bravo, Rudra Bose, Kyle J Travaglini, Victor L Lam, Darrin Goodness, Gary Dixon, Emily Marzette, Julianne Jin, Ruilin Tian, Eric Tse, Romany Abskharon, Henry Pan, Emma C Carroll, Rosalie E Lawrence, Jason E Gestwicki, David Eisenberg, Nicholas M Kanaan, Daniel R Southworth, John D Gross, Li Gan, Danielle L Swaney, Martin Kampmann

Aggregation of the protein tau defines tauopathies, which include Alzheimer's disease and frontotemporal dementia. Specific neuronal subtypes are selectively vulnerable to tau aggregation and subsequent dysfunction and death, but the underlying mechanisms are unknown. To systematically uncover the cellular factors controlling the accumulation of tau aggregates in human neurons, we conducted a genome-wide CRISPRi-based modifier screen in iPSC-derived neurons. The screen uncovered expected pathways, including autophagy, but also unexpected pathways, including UFMylation and GPI anchor synthesis. We discover that the E3 ubiquitin ligase CUL5SOCS4 is a potent modifier of tau levels in human neurons, ubiquitinates tau, and is a correlated with vulnerability to tauopathies in mouse and human. Disruption of mitochondrial function promotes proteasomal misprocessing of tau, which generates tau proteolytic fragments like those in disease and changes tau aggregation in vitro. These results reveal new principles of tau proteostasis in human neurons and pinpoint potential therapeutic targets for tauopathies.

与年龄相关的神经退行性疾病的一个标志是蛋白质的聚集。tau蛋白的聚集定义了tau病,包括阿尔茨海默病和额颞叶痴呆。特定的神经元亚型选择性地易受tau聚集体积累以及随后的功能障碍和死亡的影响。细胞类型选择性脆弱性的潜在机制尚不清楚。为了系统地揭示控制人类神经元中tau聚集体积累的细胞因子,我们在iPSC衍生的神经元中进行了全基因组CRISPRi修饰物筛选。该筛选揭示了预期的途径,包括自噬,但也揭示了控制tau寡聚物水平的意外途径,包括UFMylation和GPI锚合成。我们将E3泛素连接酶CUL5鉴定为tau相互作用因子和tau水平的有效调节剂。此外,线粒体功能的破坏增加了tau寡聚物的水平,并促进了蛋白酶体对tau的错误处理。这些结果揭示了人类神经元中tau蛋白稳定的新原理,并确定了tau病的潜在治疗靶点。
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引用次数: 0
Discovery of a multipotent cell type from the term human placenta. 从人胎盘中发现一种多能细胞。
Pub Date : 2024-11-03 DOI: 10.1101/2023.08.02.551028
Sangeetha Vadakke-Madathil, Esmaa Bouhamida, Bingyan Wang, Prabhu Mathiyalagan, Micayla Oniskey, Carlos Santos-Gallego, Michael Hadley, Lori Croft, Fumiko Dekio, Rachel Brody, Shari Gelber, Rhoda Sperling, Hina W Chaudhry

We report a population of multipotent cells isolated from term human placentas, for the first time, that differentiates into cardiomyocytes and vascular cells with clonal ability, migratory ability, and trancriptomic evidence of immune privilege. Caudal-type homeobox-2 (CDX2) is a conserved factor that regulates trophectoderm formation and placentation during early embryonic development but has not previously been implicated in developmentally conserved regenerative mechanisms. We earlier reported that murine Cdx2 cells restored cardiac function after intravenous delivery in male mice with experimental myocardial infarction (MI). Here we demonstrate that CDX2 cells found in human chorion are poised for cardiovascular differentiation. We isolated CDX2 cells from term placentas of 150 healthy patients and showed that they spontaneously differentiate into cardiomyocytes, functional vascular cells, and retain homing ability in vitro with a transcriptome that supports enhanced cardiogenesis, vasculogenesis, immune modulation, and chemotaxis gene signatures. They restore cardiac function when administered to NOD/SCID mice subjected to MI. CDX2 cells can be clonally propagated in culture with retention of cardiovascular differentiation. Our data compels further use of this ethically feasible cell source in the design of therapeutic strategies for cardiovascular disease.

我们首次报道了从人类胎盘中分离出的一组独特的多能细胞,它们可以分化为具有克隆增殖能力、迁移能力和免疫特权转录组学证据的心肌细胞和血管细胞。尾型同源盒-2(CDX2)是一种保守因子,在胚胎早期发育过程中调节滋养细胞外胚层的形成和胎盘形成,但以前从未涉及发育保守的再生机制。我们早些时候报道,在患有实验性心脏损伤(心肌梗死)的雄性小鼠中,小鼠胎盘中的Cdx2谱系细胞能够在静脉注射后恢复心脏功能。在这里,我们证明了CDX2表达细胞在人绒毛膜中普遍存在,并准备进行心血管分化。我们检测了106名健康患者的胎盘,发现分离的CDX2细胞可以自发分化为心肌细胞、功能性血管细胞,并在体外保持归巢能力。转录组学分析的功能注释支持CDX2细胞中增强的心脏生成、血管生成、免疫调节和趋化性基因特征。CDX2细胞可以在保持心血管分化的培养基中克隆繁殖。我们的数据支持在心血管疾病治疗策略的设计中进一步使用这种可获得且符合伦理的细胞源。
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引用次数: 0
Regulation of NRF2 by Phosphoinositides and Small Heat Shock Proteins. 磷酸肌苷和小热休克蛋白对NRF2的调控。
Pub Date : 2024-11-01 DOI: 10.1101/2023.10.26.564194
Changliang Chen, Mo Chen, Tianmu Wen, Poorwa Awasthi, Noah D Carrillo, Richard A Anderson, Vincent L Cryns

Reactive oxygen species (ROS) are generated by aerobic metabolism, and their deleterious effects are buffered by the cellular antioxidant response, which prevents oxidative stress. The nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator of the antioxidant response. Basal levels of NRF2 are kept low by ubiquitin-dependent degradation of NRF2 by E3 ligases, including the Kelch-like ECH-associated protein 1 (KEAP1). Here, we show that the stability and function of NRF2 is regulated by the type I phosphatidylinositol phosphate kinase γ (PIPKIγ), which binds NRF2 and transfers its product phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P 2 ) to NRF2. PtdIns(4,5)P 2 binding recruits the small heat shock protein HSP27 to the complex. Silencing PIPKIγ or HSP27 destabilizes NRF2, reduces expression of its target gene HO-1, and sensitizes cells to oxidative stress. These data demonstrate an unexpected role of phosphoinositides and HSP27 in regulating NRF2 and point to PIPKIγ and HSP27 as drug targets to destabilize NRF2 in cancer.

In brief: Phosphoinositides are coupled to NRF2 by PIPKIγ, and HSP27 is recruited and stabilizes NRF2, promoting stress-resistance.

活性氧(ROS)是由有氧代谢产生的,其有害作用被细胞抗氧化反应所缓冲,从而防止氧化应激。核因子红细胞2相关因子2 (NRF2)是抗氧化反应的主要转录调控因子。通过E3连接酶(包括kelch样ech相关蛋白1 (KEAP1))对NRF2的泛素依赖性降解,NRF2的基础水平保持在较低水平。在这里,我们发现NRF2的稳定性和功能受I型磷脂酰肌醇磷酸激酶g (PIPKIg)的调节,PIPKIg结合NRF2并将其产物磷脂酰肌醇4,5-二磷酸(PtdIns(4,5) p2)转移到NRF2。PtdIns(4,5) p2结合将小热休克蛋白HSP27招募到复合物中。沉默PIPKIg或HSP27会破坏NRF2的稳定性,降低其靶基因HO-1的表达,并使细胞对氧化应激敏感。这些数据证明了磷酸肌苷和HSP27在调节NRF2中的意想不到的作用,并指出PIPKIg和HSP27是癌症中破坏NRF2稳定的药物靶点。简而言之:磷酸肌苷通过PIPKIγ与NRF2偶联,HSP27被募集并稳定NRF2,促进抗逆性。
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引用次数: 0
Phenotypic complexities of rare heterozygous neurexin-1 deletions. 不同NRXN1+/-突变的精确治疗靶向。
Pub Date : 2024-11-01 DOI: 10.1101/2023.10.28.564543
Michael B Fernando, Yu Fan, Yanchun Zhang, Alex Tokolyi, Aleta N Murphy, Sarah Kammourh, P J Michael Deans, Sadaf Ghorbani, Ryan Onatzevitch, Adriana Pero, Christopher Padilla, Sarah Williams, Erin K Flaherty, Iya A Prytkova, Lei Cao, David A Knowles, Gang Fang, Paul A Slesinger, Kristen J Brennand

Given the large number of genes significantly associated with risk for neuropsychiatric disorders, a critical unanswered question is the extent to which diverse mutations --sometimes impacting the same gene-- will require tailored therapeutic strategies. Here we consider this in the context of rare neuropsychiatric disorder-associated copy number variants (2p16.3) resulting in heterozygous deletions in NRXN1, a pre-synaptic cell adhesion protein that serves as a critical synaptic organizer in the brain. Complex patterns of NRXN1 alternative splicing are fundamental to establishing diverse neurocircuitry, vary between the cell types of the brain, and are differentially impacted by unique (non-recurrent) deletions. We contrast the cell-type-specific impact of patient-specific mutations in NRXN1 using human induced pluripotent stem cells, finding that perturbations in NRXN1 splicing result in divergent cell-type-specific synaptic outcomes. Via distinct loss-of-function (LOF) and gain-of-function (GOF) mechanisms, NRXN1 +/- deletions cause decreased synaptic activity in glutamatergic neurons, yet increased synaptic activity in GABAergic neurons. Reciprocal isogenic manipulations causally demonstrate that aberrant splicing drives these changes in synaptic activity. For NRXN1 deletions, and perhaps more broadly, precision medicine will require stratifying patients based on whether their gene mutations act through LOF or GOF mechanisms, in order to achieve individualized restoration of NRXN1 isoform repertoires by increasing wildtype, or ablating mutant isoforms. Given the increasing number of mutations predicted to engender both LOF and GOF mechanisms in brain disorders, our findings add nuance to future considerations of precision medicine.

随着基因研究继续确定与神经精神疾病风险显著相关的风险位点,一个关键的悬而未决的问题是,不同的突变(有时影响同一基因)在多大程度上需要共同或单独定制的治疗策略。在这里,我们在罕见的、杂合的、非复发的拷贝数变异(2p16.3)的背景下考虑这一点,这些变异与影响NRXN1的各种神经精神疾病有关,NRXN1是一种突触前细胞粘附蛋白,在大脑中充当关键的突触组织者。NRXN1选择性剪接的复杂模式是建立多样化神经回路的基础,在大脑细胞类型之间存在差异,并且受到独特的患者特异性(非复发性)缺失的差异影响。精准医疗的进步可能需要以细胞类型特异性的方式恢复每个人的NRXN1亚型。为此,我们利用人诱导多能干细胞对比了NRXN1中独特的患者特异性突变对细胞类型的特异性影响。NRXN1剪接的干扰会导致不同的细胞类型特异性突触结果:尽管NRXN1 +/-缺失会导致谷氨酸能神经元成熟过程中突触活性降低,但未成熟gaba能神经元的突触活性却意外增加。谷氨酸能和氨基丁酸能突触缺陷都反映了独立的功能丧失(LOF)和功能获得(GOF)剪接缺陷。在临床相关性方面,我们发现β-雌二醇治疗增加了谷氨酸能神经元中NRXN1的表达,而反义寡核苷酸敲低了谷氨酸能和gaba能神经元中突变异构体的表达。直接或间接操作NRXN1剪接异构体为治疗人类2p16.3缺失提供了一种有希望的治疗策略。
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引用次数: 0
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