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Characterisation of premature cell senescence in Alzheimer’s disease using single nuclear transcriptomics 利用单核转录组学分析阿尔茨海默病细胞早衰的特征
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-05-02 DOI: 10.1007/s00401-024-02727-9
Nurun N. Fancy, Amy M. Smith, Alessia Caramello, Stergios Tsartsalis, Karen Davey, Robert C. J. Muirhead, Aisling McGarry, Marion H. Jenkyns, Eleonore Schneegans, Vicky Chau, Michael Thomas, Sam Boulger, To Ka Dorcas Cheung, Emily Adair, Marianna Papageorgopoulou, Nanet Willumsen, Combiz Khozoie, Diego Gomez-Nicola, Johanna S. Jackson, Paul M. Matthews

Aging is associated with cell senescence and is the major risk factor for AD. We characterized premature cell senescence in postmortem brains from non-diseased controls (NDC) and donors with Alzheimer’s disease (AD) using imaging mass cytometry (IMC) and single nuclear RNA (snRNA) sequencing (> 200,000 nuclei). We found increases in numbers of glia immunostaining for galactosidase beta (> fourfold) and p16INK4A (up to twofold) with AD relative to NDC. Increased glial expression of genes related to senescence was associated with greater β-amyloid load. Prematurely senescent microglia downregulated phagocytic pathways suggesting reduced capacity for β-amyloid clearance. Gene set enrichment and pseudo-time trajectories described extensive DNA double-strand breaks (DSBs), mitochondrial dysfunction and ER stress associated with increased β-amyloid leading to premature senescence in microglia. We replicated these observations with independent AD snRNA-seq datasets. Our results describe a burden of senescent glia with AD that is sufficiently high to contribute to disease progression. These findings support the hypothesis that microglia are a primary target for senolytic treatments in AD.

衰老与细胞衰老有关,是阿尔茨海默病的主要风险因素。我们利用成像质谱细胞仪(IMC)和单核糖核酸(snRNA)测序(20 万个细胞核)研究了非患病对照组(NDC)和阿尔茨海默病(AD)供体死后大脑中细胞过早衰老的特征。我们发现,相对于 NDC,AD 患者神经胶质免疫染色半乳糖苷酶 beta(4 倍)和 p16INK4A(2 倍)的数量增加。衰老相关基因的胶质表达增加与β-淀粉样蛋白负荷增加有关。过早衰老的小胶质细胞下调了吞噬途径,这表明清除β淀粉样蛋白的能力下降。基因组富集和伪时间轨迹描述了与导致小胶质细胞过早衰老的β淀粉样蛋白增加相关的广泛DNA双链断裂(DSB)、线粒体功能障碍和ER应激。我们用独立的 AD snRNA-seq 数据集重复了这些观察结果。我们的研究结果表明,AD 患者的衰老胶质细胞负担很重,足以导致疾病进展。这些发现支持了小胶质细胞是AD衰老治疗的主要靶点这一假设。
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引用次数: 0
Viral entry and translation in brain endothelia provoke influenza-associated encephalopathy 脑内皮细胞中的病毒进入和翻译引发流感相关脑病
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-30 DOI: 10.1007/s00401-024-02723-z
Shihoko Kimura-Ohba, Mieko Kitamura, Yusuke Tsukamoto, Shigetoyo Kogaki, Shinsuke Sakai, Hiroaki Fushimi, Keiko Matsuoka, Makoto Takeuchi, Kyoko Itoh, Keiji Ueda, Tomonori Kimura

Influenza-associated encephalopathy (IAE) is extremely acute in onset, with high lethality and morbidity within a few days, while the direct pathogenesis by influenza virus in this acute phase in the brain is largely unknown. Here we show that influenza virus enters into the cerebral endothelium and thereby induces IAE. Three-weeks-old young mice were inoculated with influenza A virus (IAV). Physical and neurological scores were recorded and temporal-spatial analyses of histopathology and viral studies were performed up to 72 h post inoculation. Histopathological examinations were also performed using IAE human autopsy brains. Viral infection, proliferation and pathogenesis were analyzed in cell lines of endothelium and astrocyte. The effects of anti-influenza viral drugs were tested in the cell lines and animal models. Upon intravenous inoculation of IAV in mice, the mice developed encephalopathy with brain edema and pathological lesions represented by micro bleeding and injured astrocytic process (clasmatodendrosis) within 72 h. Histologically, massive deposits of viral nucleoprotein were observed as early as 24 h post infection in the brain endothelial cells of mouse models and the IAE patients. IAV inoculated endothelial cell lines showed deposition of viral proteins and provoked cell death, while IAV scarcely amplified. Inhibition of viral transcription and translation suppressed the endothelial cell death and the lethality of mouse models. These data suggest that the onset of encephalopathy should be induced by cerebral endothelial infection with IAV. Thus, IAV entry into the endothelium, and transcription and/or translation of viral RNA, but not viral proliferation, should be the key pathogenesis of IAE.

流感相关脑病(IAE)起病极为急骤,在数天内致死率和发病率都很高,而流感病毒在脑部急性期的直接致病机理尚不清楚。在这里,我们发现流感病毒进入脑内皮细胞,从而诱发 IAE。给三周大的幼鼠接种甲型流感病毒(IAV)。记录小鼠的体格和神经评分,并在接种后 72 小时内对组织病理学和病毒研究进行时空分析。此外,还使用 IAE 人体解剖脑进行了组织病理学检查。在内皮细胞和星形胶质细胞系中分析了病毒感染、增殖和致病机理。在细胞系和动物模型中测试了抗流感病毒药物的效果。给小鼠静脉注射 IAV 后,小鼠在 72 小时内发生脑病,出现脑水肿和病理病变,表现为微量出血和星形胶质细胞损伤(clasmatodendrosis)。接种 IAV 的内皮细胞系出现病毒蛋白沉积并导致细胞死亡,而 IAV 几乎没有扩增。抑制病毒转录和翻译可抑制内皮细胞死亡和小鼠模型的致死率。这些数据表明,脑病的发生应是由脑内皮感染 IAV 引发的。因此,IAV 进入内皮、病毒 RNA 的转录和/或翻译,而不是病毒增殖,应该是 IAE 的关键发病机制。
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引用次数: 0
Stage-dependent immunity orchestrates AQP4 antibody-guided NMOSD pathology: a role for netting neutrophils with resident memory T cells in situ 阶段依赖性免疫协调AQP4抗体引导的NMOSD病理学:中性粒细胞与驻留记忆T细胞在原位网状结构中的作用
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-24 DOI: 10.1007/s00401-024-02725-x
Akihiro Nakajima, Fumihiro Yanagimura, Etsuji Saji, Hiroshi Shimizu, Yasuko Toyoshima, Kaori Yanagawa, Musashi Arakawa, Mariko Hokari, Akiko Yokoseki, Takahiro Wakasugi, Kouichirou Okamoto, Hirohide Takebayashi, Chihiro Fujii, Kyoko Itoh, Yo-ichi Takei, Shinji Ohara, Mitsunori Yamada, Hitoshi Takahashi, Masatoyo Nishizawa, Hironaka Igarashi, Akiyoshi Kakita, Osamu Onodera, Izumi Kawachi

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the CNS characterized by the production of disease-specific autoantibodies against aquaporin-4 (AQP4) water channels. Animal model studies suggest that anti-AQP4 antibodies cause a loss of AQP4-expressing astrocytes, primarily via complement-dependent cytotoxicity. Nonetheless, several aspects of the disease remain unclear, including: how anti-AQP4 antibodies cross the blood–brain barrier from the periphery to the CNS; how NMOSD expands into longitudinally extensive transverse myelitis or optic neuritis; how multiphasic courses occur; and how to prevent attacks without depleting circulating anti-AQP4 antibodies, especially when employing B-cell-depleting therapies. To address these knowledge gaps, we conducted a comprehensive ‘stage-dependent’ investigation of immune cell elements in situ in human NMOSD lesions, based on neuropathological techniques for autopsied/biopsied CNS materials. The present study provided three major findings. First, activated or netting neutrophils and melanoma cell adhesion molecule-positive (MCAM+) helper T (TH) 17/cytotoxic T (TC) 17 cells are prominent, and the numbers of these correlate with the size of NMOSD lesions in the initial or early-active stages. Second, forkhead box P3-positive (FOXP3+) regulatory T (Treg) cells are recruited to NMOSD lesions during the initial, early-active or late-active stages, suggesting rapid suppression of proinflammatory autoimmune events in the active stages of NMOSD. Third, compartmentalized resident memory immune cells, including CD103+ tissue-resident memory T (TRM) cells with long-lasting inflammatory potential, are detected under “standby” conditions in all stages. Furthermore, CD103+ TRM cells express high levels of granzyme B/perforin-1 in the initial or early-active stages of NMOSD in situ. We infer that stage-dependent compartmentalized immune traits orchestrate the pathology of anti-AQP4 antibody-guided NMOSD in situ. Our work further suggests that targeting activated/netting neutrophils, MCAM+ TH17/TC17 cells, and CD103+ TRM cells, as well as promoting the expansion of FOXP3+ Treg cells, may be effective in treating and preventing relapses of NMOSD.

神经脊髓炎视网膜频谱紊乱症(NMOSD)是一种中枢神经系统自身免疫性疾病,其特征是产生针对水通道(AQP4)的疾病特异性自身抗体。动物模型研究表明,抗 AQP4 抗体主要通过补体依赖性细胞毒性导致表达 AQP4 的星形胶质细胞丧失。然而,该病的几个方面仍不清楚,包括:抗 AQP4 抗体如何从外周穿过血脑屏障进入中枢神经系统;NMOSD 如何扩展为纵向广泛的横贯性脊髓炎或视神经炎;多相病程如何发生;以及如何在不消耗循环中的抗 AQP4 抗体的情况下预防发作,尤其是在采用 B 细胞消耗疗法时。为了填补这些知识空白,我们基于对尸检/活检中枢神经系统材料的神经病理学技术,对人类 NMOSD 病变部位的免疫细胞元素进行了全面的 "阶段性 "调查。本研究有三大发现。首先,活化或网状中性粒细胞和黑色素瘤细胞粘附分子阳性(MCAM+)辅助性 T(TH)17/毒性 T(TC)17 细胞非常突出,其数量与初期或早期活动期 NMOSD 病变的大小相关。其次,叉头盒 P3 阳性(FOXP3+)的调节性 T(Treg)细胞在初期、早期活动期或晚期活动期被招募到 NMOSD 病变部位,这表明在 NMOSD 的活动期,促炎性自身免疫事件被迅速抑制。第三,在所有阶段的 "待机 "状态下都能检测到分区常驻记忆免疫细胞,包括具有长期炎症潜能的 CD103+ 组织常驻记忆 T(TRM)细胞。此外,CD103+ TRM 细胞在原位 NMOSD 的初始或早期活动阶段表达高水平的颗粒酶 B/穿孔素-1。我们推断,抗 AQP4 抗体引导的原位 NMOSD 的病理过程是由阶段依赖性的区隔化免疫特征协调的。我们的研究进一步表明,针对活化/成网的中性粒细胞、MCAM+ TH17/TC17 细胞和 CD103+ TRM 细胞,以及促进 FOXP3+ Treg 细胞的扩增,可能会有效治疗和预防 NMOSD 复发。
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引用次数: 0
BTK inhibition limits microglia-perpetuated CNS inflammation and promotes myelin repair 抑制 BTK 可限制小胶质细胞引发的中枢神经系统炎症并促进髓鞘修复
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-24 DOI: 10.1007/s00401-024-02730-0
Anastasia Geladaris, Sebastian Torke, Darius Saberi, Yasemin B. Alankus, Frank Streit, Sabrina Zechel, Christine Stadelmann-Nessler, Andreas Fischer, Ursula Boschert, Darius Häusler, Martin S. Weber

In multiple sclerosis (MS), persisting disability can occur independent of relapse activity or development of new central nervous system (CNS) inflammatory lesions, termed chronic progression. This process occurs early and it is mostly driven by cells within the CNS. One promising strategy to control progression of MS is the inhibition of the enzyme Bruton's tyrosine kinase (BTK), which is centrally involved in the activation of both B cells and myeloid cells, such as macrophages and microglia. The benefit of BTK inhibition by evobrutinib was shown as we observed reduced pro-inflammatory activation of microglia when treating chronic experimental autoimmune encephalomyelitis (EAE) or following the adoptive transfer of activated T cells. Additionally, in a model of toxic demyelination, evobrutinib-mediated BTK inhibition promoted the clearance of myelin debris by microglia, leading to an accelerated remyelination. These findings highlight that BTK inhibition has the potential to counteract underlying chronic progression of MS.

在多发性硬化症(MS)中,持续性残疾的发生可能与复发活动或新的中枢神经系统(CNS)炎性病变的发展无关,这被称为慢性进展。这一过程发生较早,主要由中枢神经系统内的细胞驱动。抑制布鲁顿酪氨酸激酶(BTK)是控制多发性硬化症进展的一种很有前景的策略,该酶主要参与 B 细胞和骨髓细胞(如巨噬细胞和小胶质细胞)的活化。在治疗慢性实验性自身免疫性脑脊髓炎(EAE)或活化T细胞收养性转移后,我们观察到小胶质细胞的促炎性活化减少,这证明了evobrutinib抑制BTK的益处。此外,在毒性脱髓鞘模型中,evobrutinib介导的BTK抑制促进了小胶质细胞对髓鞘碎片的清除,从而加速了髓鞘再形成。这些发现突出表明,抑制 BTK 有可能抵消多发性硬化症潜在的慢性进展。
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引用次数: 0
Nanopore sequencing from formalin-fixed paraffin-embedded specimens for copy-number profiling and methylation-based CNS tumor classification 对福尔马林固定石蜡包埋标本进行纳米孔测序,用于拷贝数分析和基于甲基化的中枢神经系统肿瘤分类
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-20 DOI: 10.1007/s00401-024-02731-z
Ann-Kristin Afflerbach, Anne Albers, Anton Appelt, Leonille Schweizer, Werner Paulus, Michael Bockmayr, Ulrich Schüller, Christian Thomas
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引用次数: 0
Abundant transcriptomic alterations in the human cerebellum of patients with a C9orf72 repeat expansion C9orf72重复扩增患者小脑中的大量转录组改变
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-19 DOI: 10.1007/s00401-024-02720-2
Evan Udine, Mariely DeJesus-Hernandez, Shulan Tian, Sofia Pereira das Neves, Richard Crook, NiCole A. Finch, Matthew C. Baker, Cyril Pottier, Neill R. Graff-Radford, Bradley F. Boeve, Ronald C. Petersen, David S. Knopman, Keith A. Josephs, Björn Oskarsson, Sandro Da Mesquita, Leonard Petrucelli, Tania F. Gendron, Dennis W. Dickson, Rosa Rademakers, Marka van Blitterswijk

The most prominent genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is a repeat expansion in the gene C9orf72. Importantly, the transcriptomic consequences of the C9orf72 repeat expansion remain largely unclear. Here, we used short-read RNA sequencing (RNAseq) to profile the cerebellar transcriptome, detecting alterations in patients with a C9orf72 repeat expansion. We focused on the cerebellum, since key C9orf72-related pathologies are abundant in this neuroanatomical region, yet TDP-43 pathology and neuronal loss are minimal. Consistent with previous work, we showed a reduction in the expression of the C9orf72 gene and an elevation in homeobox genes, when comparing patients with the expansion to both patients without the C9orf72 repeat expansion and control subjects. Interestingly, we identified more than 1000 alternative splicing events, including 4 in genes previously associated with ALS and/or FTLD. We also found an increase of cryptic splicing in C9orf72 patients compared to patients without the expansion and controls. Furthermore, we demonstrated that the expression level of select RNA-binding proteins is associated with cryptic splice junction inclusion. Overall, this study explores the presence of widespread transcriptomic changes in the cerebellum, a region not confounded by severe neurodegeneration, in post-mortem tissue from C9orf72 patients.

肌萎缩侧索硬化症(ALS)和额颞叶变性(FTLD)最主要的遗传病因是基因 C9orf72 的重复扩增。重要的是,C9orf72重复扩增的转录组学后果在很大程度上仍不清楚。在这里,我们使用短线程 RNA 测序(RNAseq)分析了小脑转录组,检测了 C9orf72 重复扩增患者的转录组变化。我们将研究重点放在了小脑上,因为在这一神经解剖区域,与 C9orf72 相关的关键病变非常多,而 TDP-43 病变和神经元丢失却很少。与之前的研究结果一致,我们发现在将C9orf72基因扩增的患者与没有C9orf72重复扩增的患者和对照组进行比较时,C9orf72基因的表达量减少,而同源染色体基因的表达量增加。有趣的是,我们发现了 1000 多个替代剪接事件,其中包括 4 个以前与 ALS 和/或 FTLD 相关的基因。我们还发现,与无 C9orf72 重复扩增的患者和对照组相比,C9orf72 患者的隐性剪接增加了。此外,我们还证明,选择性 RNA 结合蛋白的表达水平与隐性剪接接头的包含有关。总之,本研究探讨了 C9orf72 患者死后组织中的小脑(一个不受严重神经变性影响的区域)是否存在广泛的转录组变化。
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引用次数: 0
Characterization of NEB pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects 患者体内 NEB 致病变体的特征揭示了新型神经性肌病的发病机制和奥美卡米肼的作用力效应
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-18 DOI: 10.1007/s00401-024-02726-w
Esmat Karimi, Jochen Gohlke, Mila van der Borgh, Johan Lindqvist, Zaynab Hourani, Justin Kolb, Stacy Cossette, Michael W. Lawlor, Coen Ottenheijm, Henk Granzier

Nebulin, a critical protein of the skeletal muscle thin filament, plays important roles in physiological processes such as regulating thin filament length (TFL), cross-bridge cycling, and myofibril alignment. Pathogenic variants in the nebulin gene (NEB) cause NEB-based nemaline myopathy (NEM2), a genetically heterogeneous disorder characterized by hypotonia and muscle weakness, currently lacking curative therapies. In this study, we examined a cohort of ten NEM2 patients, each with unique pathogenic variants, aiming to understand their impact on mRNA, protein, and functional levels. Results show that pathogenic truncation variants affect NEB mRNA stability and lead to nonsense-mediated decay of the mutated transcript. Moreover, a high incidence of cryptic splice site activation was found in patients with pathogenic splicing variants that are expected to disrupt the actin-binding sites of nebulin. Determination of protein levels revealed patients with either relatively normal or markedly reduced nebulin. We observed a positive relation between the reduction in nebulin and a reduction in TFL, or reduction in tension (both maximal and submaximal tension). Interestingly, our study revealed a pathogenic duplication variant in nebulin that resulted in a four-copy gain in the triplicate region of NEB and a much larger nebulin protein and longer TFL. Additionally, we investigated the effect of Omecamtiv mecarbil (OM), a small-molecule activator of cardiac myosin, on force production of type 1 muscle fibers of NEM2 patients. OM treatment substantially increased submaximal tension across all NEM2 patients ranging from 87 to 318%, with the largest effects in patients with the lowest level of nebulin. In summary, this study indicates that post-transcriptional or post-translational mechanisms regulate nebulin expression. Moreover, we propose that the pathomechanism of NEM2 involves not only shortened but also elongated thin filaments, along with the disruption of actin-binding sites resulting from pathogenic splicing variants. Significantly, our findings highlight the potential of OM treatment to improve skeletal muscle function in NEM2 patients, especially those with large reductions in nebulin levels.

Nebulin 是骨骼肌细丝的一种重要蛋白质,在调节细丝长度(TFL)、横桥循环和肌原纤维排列等生理过程中发挥着重要作用。nebulin基因(NEB)的致病变体会导致基于NEB的神经性肌病(NEM2),这是一种以肌张力低下和肌无力为特征的遗传异质性疾病,目前尚无治疗方法。在这项研究中,我们对十名 NEM2 患者进行了研究,每名患者都有独特的致病变异,目的是了解这些变异对 mRNA、蛋白质和功能水平的影响。结果显示,致病性截断变体会影响 NEB mRNA 的稳定性,并导致变异转录本的无义介导衰变。此外,在患有致病性剪接变异的患者中发现,隐性剪接位点激活的发生率很高,而这种剪接变异预计会破坏球蛋白的肌动蛋白结合位点。蛋白质水平的测定显示,患者的球蛋白要么相对正常,要么明显减少。我们观察到,球蛋白的减少与 TFL 的减少或张力(最大张力和亚最大张力)的减少之间存在正相关。有趣的是,我们的研究发现了 nebulin 的一个致病性重复变体,该变体导致 NEB 的三倍区出现四个拷贝的增益,并导致 nebulin 蛋白变大和 TFL 变长。此外,我们还研究了 Omecamtiv mecarbil(OM)(一种小分子心肌肌球蛋白激活剂)对 NEM2 患者 1 型肌纤维力量产生的影响。OM 治疗可大幅提高所有 NEM2 患者的亚极限张力,提高幅度从 87% 到 318% 不等,其中对 Nebulin 水平最低的患者影响最大。总之,这项研究表明,转录后或翻译后机制可调控 nebulin 的表达。此外,我们还提出,NEM2 的病理机制不仅涉及细丝的缩短,还涉及细丝的拉长,以及致病剪接变体导致的肌动蛋白结合位点的破坏。重要的是,我们的研究结果凸显了 OM 治疗改善 NEM2 患者骨骼肌功能的潜力,尤其是那些球蛋白水平大幅降低的患者。
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引用次数: 0
Histologic correlates of “Choroidal abnormalities” in Neurofibromatosis type 1 (NF1) 1 型神经纤维瘤病 (NF1) 中 "脉络膜异常 "的组织学相关性
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-12 DOI: 10.1007/s00401-024-02724-y
Anat O. Stemmer-Rachamimov, Liana Kozanno, Scott R. Plotkin, Justin T. Jordan, Joseph F. 3rd Rizzo

Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disorder characterized by proliferation of cells from neural crest origin. The most common manifestations are cutaneous, neurologic, skeletal and ocular. The distinction of NF1 from other syndromes with multiple café-au-lait macules may be difficult in the pediatric age group, and ocular findings, especially Lisch nodules (i.e., melanocytic hamartomas on the irides), are a useful, early diagnostic tool. In recent years, novel ocular manifestations descriptively referred to as “choroidal abnormalities”, choroidal “hyperpigmented spots” and “retinal vascular abnormalities” have been recognized in NF1. Choroidal abnormalities (CA) appear as bright patchy nodules that can be best detected with near-infrared ocular coherence tomography imaging (NIR-OCT). Because of their high specificity and sensitivity for NF1, CA have been added as an ocular diagnostic criterion of NF1 as an alternative to Lisch nodules. Although CA are important ocular diagnostic criteria for NF1, the histologic correlates are controversial. We present the postmortem ocular pathology findings of an NF1 patient for whom clinical notes and ocular imaging were available. Findings in this patient included choroidal hyperpigmented spots on funduscopy and retinal vascular abnormalities, both of which have been reported to be closely associated with CA. Histologic examination of the eyes showed multiple clusters of melanocytes of varying sizes in the choroid. Pathologic review of 12 additional postmortem eyes from 6 NF1 patients showed multiple, bilateral choroidal melanocytic aggregates in all eyes. These findings suggest that the CA seen on NIR-OCT and the hyperpigmented spots seen clinically in NF1 patients are manifestations of multifocal choroidal melanocytic clusters, consistent with choroidal melanocytic hamartomas. Lisch nodules, often multiple, were present in all eyes with morphology that differed from the choroidal hamartomas. As such, although CA and Lisch nodules are melanocytic hamartomas, there are clear phenotypical differences in their morphologies.

神经纤维瘤病 1 型(NF1)是一种罕见的常染色体显性遗传疾病,其特征是神经嵴起源细胞的增殖。最常见的表现是皮肤、神经、骨骼和眼部。在儿科年龄组中,NF1 与其他伴有多发性咖啡色斑块的综合征可能难以区分,而眼部检查结果,尤其是 Lisch 结节(即虹膜上的黑素细胞瘤),是一种有用的早期诊断工具。近年来,在 NF1 患者中发现了描述性的 "脉络膜异常"、脉络膜 "色素沉着斑 "和 "视网膜血管异常 "等新的眼部表现。脉络膜异常(CA)表现为明亮的斑块状结节,近红外眼相干断层扫描成像(NIR-OCT)可对其进行最佳检测。由于脉络膜异常对 NF1 的特异性和敏感性都很高,因此已被列为 NF1 的眼部诊断标准,以替代 Lisch 结节。尽管 CA 是 NF1 重要的眼部诊断标准,但其组织学相关性仍存在争议。我们介绍了一名 NF1 患者的尸检眼部病理结果,该患者的临床病历和眼部影像学检查结果均可提供。该患者的眼底检查结果包括脉络膜色素沉着斑和视网膜血管异常,据报道,这两种情况都与CA密切相关。眼球组织学检查显示,脉络膜上有多个大小不等的黑色素细胞团。对另外 12 只来自 6 名 NF1 患者的死后眼球进行的病理检查显示,所有眼球中都有多发性、双侧脉络膜黑色素细胞聚集。这些发现表明,NIR-OCT 上看到的 CA 和 NF1 患者临床上看到的色素沉着斑是多灶性脉络膜黑色素细胞团的表现,与脉络膜黑色素细胞仓瘤一致。Lisch结节通常是多发性的,存在于所有眼球中,其形态与脉络膜仓细胞瘤不同。因此,虽然CA和Lisch结节都是黑素细胞仓细胞瘤,但它们的形态存在明显的表型差异。
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引用次数: 0
Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer’s disease 纤连蛋白 1 (FN1) 的罕见遗传变异可预防阿尔茨海默病中的 APOEε4
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-10 DOI: 10.1007/s00401-024-02721-1
Prabesh Bhattarai, Tamil Iniyan Gunasekaran, Michael E. Belloy, Dolly Reyes-Dumeyer, Dörthe Jülich, Hüseyin Tayran, Elanur Yilmaz, Delaney Flaherty, Bengisu Turgutalp, Gauthaman Sukumar, Camille Alba, Elisa Martinez McGrath, Daniel N. Hupalo, Dagmar Bacikova, Yann Le Guen, Rafael Lantigua, Martin Medrano, Diones Rivera, Patricia Recio, Tal Nuriel, Nilüfer Ertekin-Taner, Andrew F. Teich, Dennis W. Dickson, Scott Holley, Michael Greicius, Clifton L. Dalgard, Michael Zody, Richard Mayeux, Caghan Kizil, Badri N. Vardarajan

The risk of developing Alzheimer’s disease (AD) significantly increases in individuals carrying the APOEε4 allele. Elderly cognitively healthy individuals with APOEε4 also exist, suggesting the presence of cellular mechanisms that counteract the pathological effects of APOEε4; however, these mechanisms are unknown. We hypothesized that APOEε4 carriers without dementia might carry genetic variations that could protect them from developing APOEε4-mediated AD pathology. To test this, we leveraged whole-genome sequencing (WGS) data in the National Institute on Aging Alzheimer's Disease Family Based Study (NIA-AD FBS), Washington Heights/Inwood Columbia Aging Project (WHICAP), and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) cohorts and identified potentially protective variants segregating exclusively among unaffected APOEε4 carriers. In homozygous unaffected carriers above 70 years old, we identified 510 rare coding variants. Pathway analysis of the genes harboring these variants showed significant enrichment in extracellular matrix (ECM)-related processes, suggesting protective effects of functional modifications in ECM proteins. We prioritized two genes that were highly represented in the ECM-related gene ontology terms, (FN1) and collagen type VI alpha 2 chain (COL6A2) and are known to be expressed at the blood–brain barrier (BBB), for postmortem validation and in vivo functional studies. An independent analysis in a large cohort of 7185 APOEε4 homozygous carriers found that rs140926439 variant in FN1 was protective of AD (OR = 0.29; 95% CI [0.11, 0.78], P = 0.014) and delayed age at onset of disease by 3.37 years (95% CI [0.42, 6.32], P = 0.025). The FN1 and COL6A2 protein levels were increased at the BBB in APOEε4 carriers with AD. Brain expression of cognitively unaffected homozygous APOEε4 carriers had significantly lower FN1 deposition and less reactive gliosis compared to homozygous APOEε4 carriers with AD, suggesting that FN1 might be a downstream driver of APOEε4-mediated AD-related pathology and cognitive decline. To validate our findings, we used zebrafish models with loss-of-function (LOF) mutations in fn1b—the ortholog for human FN1. We found that fibronectin LOF reduced gliosis, enhanced gliovascular remodeling, and potentiated the microglial response, suggesting that pathological accumulation of FN1 could impair toxic protein clearance, which is ameliorated with FN1 LOF. Our study suggests that vascular deposition of FN1 is related to the pathogenicity of APOEε4, and LOF variants in FN1 may reduce APOEε4-related AD risk, providing novel clues to potential therapeutic interventions targeting the ECM to mitigate AD risk.

携带 APOEε4 等位基因的人患阿尔茨海默病(AD)的风险明显增加。也存在认知能力健康的老年 APOEε4 携带者,这表明存在抵消 APOEε4 病理效应的细胞机制;然而,这些机制尚不清楚。我们假设,没有痴呆症的 APOEε4 携带者可能携带有基因变异,这些变异可以保护他们免于发展 APOEε4 介导的 AD 病理学。为了验证这一点,我们利用了美国国家老龄化研究所阿尔茨海默病家族研究(NIA-AD FBS)、华盛顿高地/因伍德哥伦比亚老龄化项目(WHICAP)和阿尔茨海默病家族遗传影响研究(EFIGA)队列中的全基因组测序(WGS)数据,发现了仅在未受影响的 APOEε4 携带者中存在的潜在保护性变异。在 70 岁以上未受影响的同源基因携带者中,我们发现了 510 个罕见的编码变异。对携带这些变异的基因进行的通路分析表明,与细胞外基质(ECM)相关的过程显著富集,这表明 ECM 蛋白的功能修饰具有保护作用。我们优先选择了两个在 ECM 相关基因本体术语(FN1 和Ⅵ型胶原蛋白α2 链 (COL6A2))中具有较高代表性且已知在血脑屏障 (BBB) 上表达的基因进行尸检验证和体内功能研究。一项对 7185 名 APOEε4 同源携带者组成的大型队列进行的独立分析发现,FN1 的 rs140926439 变异对 AD 有保护作用(OR = 0.29;95% CI [0.11,0.78],P = 0.014),并可将发病年龄推迟 3.37 年(95% CI [0.42,6.32],P = 0.025)。在AD APOEε4携带者中,BBB的FN1和COL6A2蛋白水平升高。与患有AD的同卵APOEε4携带者相比,认知能力未受影响的同卵APOEε4携带者的脑表达中FN1沉积明显较低,反应性胶质细胞病变也较少,这表明FN1可能是APOEε4介导的AD相关病理和认知能力下降的下游驱动因素。为了验证我们的发现,我们使用了功能缺失(LOF)突变的斑马鱼模型--fn1b是人类FN1的直向同源物。我们发现,纤连蛋白功能缺失突变减少了神经胶质的形成,加强了神经胶质血管的重塑,并增强了微胶质细胞的反应,这表明 FN1 的病理积累可能会影响毒性蛋白的清除,而 FN1 功能缺失突变则会改善这种情况。我们的研究表明,FN1的血管沉积与APOEε4的致病性有关,而FN1的LOF变异可能会降低APOEε4相关的AD风险,这为针对ECM的潜在治疗干预提供了新的线索,从而降低了AD风险。
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引用次数: 0
Metabologenomic characterization uncovers a clinically aggressive IDH mutant glioma subtype 代谢组学特征发现了一种临床侵袭性IDH突变胶质瘤亚型
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-07 DOI: 10.1007/s00401-024-02713-1
Farshad Nassiri, Andrew Ajisebutu, Vikas Patil, Yasin Mamatjan, Jeff Liu, Justin Z. Wang, Mathew R. Voisin, Romina Nejad, Sheila Mansouri, Shirin Karimi, Ankur Chakravarthy, Eric Chen, Daniel D. De Carvalho, Kenneth Aldape, Gelareh Zadeh

Mutations in the pivotal metabolic isocitrate dehydrogenase (IDH) enzymes are recognized to drive the molecular footprint of diffuse gliomas, and patients with IDH mutant gliomas have overall favorable outcomes compared to patients with IDH wild-type tumors. However, survival still varies widely among patients with IDH mutated tumors. Here, we aimed to characterize molecular signatures that explain the range of IDH mutant gliomas. By integrating matched epigenome-wide methylome, transcriptome, and global metabolome data in 154 patients with gliomas, we identified a group of IDH mutant gliomas with globally altered metabolism that resembled IDH wild-type tumors. IDH-mutant gliomas with altered metabolism have significantly shorter overall survival from their IDH mutant counterparts that is not fully accounted for by recognized molecular prognostic markers of CDKN2A/B loss and glioma CpG Island Methylator Phenotype (GCIMP) status. IDH-mutant tumors with dysregulated metabolism harbored distinct epigenetic alterations that converged to drive proliferative and stem-like transcriptional profiles, providing a window to target novel dependencies in gliomas.

Graphical Abstract

摘要 重要的代谢性异柠檬酸脱氢酶(IDH)中的突变被认为是弥漫性胶质瘤分子足迹的驱动因素,与IDH野生型肿瘤患者相比,IDH突变胶质瘤患者的总体预后良好。然而,IDH突变肿瘤患者的生存率仍有很大差异。在这里,我们旨在描述能解释IDH突变胶质瘤范围的分子特征。通过整合154名胶质瘤患者的全表观基因组甲基组、转录组和全代谢组数据,我们发现了一组新陈代谢发生全面改变的IDH突变胶质瘤,它们与IDH野生型肿瘤相似。新陈代谢发生改变的IDH突变型胶质瘤的总生存期明显短于IDH突变型胶质瘤,而CDKN2A/B缺失和胶质瘤CpG岛甲基化表型(GCIMP)状态这些公认的分子预后标志物并不能完全解释这一现象。新陈代谢失调的IDH突变肿瘤隐藏着不同的表观遗传学改变,这些改变共同驱动着增殖性和干细胞样转录特征,为靶向胶质瘤中的新型依赖关系提供了一个窗口。 图表摘要
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