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Autophagy–lysosomal-associated neuronal death in neurodegenerative disease 神经退行性疾病中与自噬-溶酶体相关的神经元死亡
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-11 DOI: 10.1007/s00401-024-02799-7
Ralph A. Nixon

Autophagy, the major lysosomal pathway for degrading damaged or obsolete constituents, protects neurons by eliminating toxic organelles and peptides, restoring nutrient and energy homeostasis, and inhibiting apoptosis. These functions are especially vital in neurons, which are postmitotic and must survive for many decades while confronting mounting challenges of cell aging. Autophagy failure, especially related to the declining lysosomal (“phagy”) functions, heightens the neuron’s vulnerability to genetic and environmental factors underlying Alzheimer’s disease (AD) and other late-age onset neurodegenerative diseases. Components of the global autophagy–lysosomal pathway and the closely integrated endolysosomal system are increasingly implicated as primary targets of these disorders. In AD, an imbalance between heightened autophagy induction and diminished lysosomal function in highly vulnerable pyramidal neuron populations yields an intracellular lysosomal build-up of undegraded substrates, including APP-βCTF, an inhibitor of lysosomal acidification, and membrane-damaging Aβ peptide. In the most compromised of these neurons, β-amyloid accumulates intraneuronally in plaque-like aggregates that become extracellular senile plaques when these neurons die, reflecting an “inside-out” origin of amyloid plaques seen in human AD brain and in mouse models of AD pathology. In this review, the author describes the importance of lysosomal-dependent neuronal cell death in AD associated with uniquely extreme autophagy pathology (PANTHOS) which is described as triggered by lysosomal membrane permeability during the earliest “intraneuronal” stage of AD. Effectors of other cell death cascades, notably calcium-activated calpains and protein kinases, contribute to lysosomal injury that induces leakage of cathepsins and activation of additional death cascades. Subsequent events in AD, such as microglial invasion and neuroinflammation, induce further cytotoxicity. In major neurodegenerative disease models, neuronal death and ensuing neuropathologies are substantially remediable by reversing underlying primary lysosomal deficits, thus implicating lysosomal failure and autophagy dysfunction as primary triggers of lysosomal-dependent cell death and AD pathogenesis and as promising therapeutic targets.

自噬是降解受损或过时成分的主要溶酶体途径,它通过消除有毒细胞器和多肽、恢复营养和能量平衡以及抑制细胞凋亡来保护神经元。这些功能对神经元尤为重要,因为神经元是后遗神经元,必须存活几十年,同时还要面对细胞衰老带来的越来越多的挑战。自噬功能失效,尤其是溶酶体("吞噬")功能下降,会使神经元更容易受到阿尔茨海默病(AD)和其他晚期神经退行性疾病的遗传和环境因素的影响。全球自噬-溶酶体途径和紧密结合的内溶酶体系统的组成成分越来越多地被认为是这些疾病的主要靶点。在多发性硬化症中,高度脆弱的锥体神经元群中自噬诱导增强和溶酶体功能减弱之间的不平衡导致细胞内溶酶体未降解底物堆积,包括溶酶体酸化抑制剂APP-βCTF和膜损伤性Aβ肽。在这些受损最严重的神经元中,β-淀粉样蛋白在神经元内积聚成斑块样聚集体,当这些神经元死亡时,这些聚集体就会变成细胞外老年斑,这反映了人类AD大脑和小鼠AD病理模型中淀粉样斑块的 "内向外 "起源。在这篇综述中,作者描述了溶酶体依赖性神经元细胞死亡在与独特的极端自噬病理学(PANTHOS)相关的AD中的重要性,这种病理学被描述为在AD最早的 "神经元内 "阶段由溶酶体膜通透性引发。其他细胞死亡级联的效应因子,特别是钙激活的钙蛋白酶和蛋白激酶,会导致溶酶体损伤,诱发酪蛋白渗漏并激活其他死亡级联。AD 的后续事件,如小胶质细胞入侵和神经炎症,会诱发进一步的细胞毒性。在主要的神经退行性疾病模型中,通过逆转潜在的原发性溶酶体缺陷,神经元死亡和随之而来的神经病理变化可以得到很大程度的补救,因此溶酶体失效和自噬功能障碍是溶酶体依赖性细胞死亡和 AD 发病机制的主要触发因素,也是很有希望的治疗靶点。
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引用次数: 0
Multiciliated ependymal cells: an update on biology and pathology in the adult brain 多纤毛上皮细胞:成人大脑生物学和病理学的最新进展
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-10 DOI: 10.1007/s00401-024-02784-0
Adam M. R. Groh, Yeji Lori Song, Fiona Tea, Brianna Lu, Stephanie Huynh, Elia Afanasiev, Maxime Bigotte, Marc R. Del Bigio, Jo Jo Anne Stratton

Mature multiciliated ependymal cells line the cerebral ventricles where they form a partial barrier between the cerebrospinal fluid (CSF) and brain parenchyma and regulate local CSF microcirculation through coordinated ciliary beating. Although the ependyma is a highly specialized brain interface with barrier, trophic, and perhaps even regenerative capacity, it remains a misfit in the canon of glial neurobiology. We provide an update to seminal reviews in the field by conducting a scoping review of the post-2010 mature multiciliated ependymal cell literature. We delineate how recent findings have either called into question or substantiated classical views of the ependymal cell. Beyond this synthesis, we document the basic methodologies and study characteristics used to describe multiciliated ependymal cells since 1980. Our review serves as a comprehensive resource for future investigations of mature multiciliated ependymal cells.

成熟的多纤毛上皮细胞排列在脑室中,它们在脑脊液(CSF)和脑实质之间形成部分屏障,并通过协调的纤毛跳动调节局部 CSF 微循环。尽管外膜是一个高度特化的脑界面,具有屏障、营养甚至再生能力,但它在神经胶质生物学中仍然是一个不合适的部分。我们对 2010 年后的成熟多纤毛外膜细胞文献进行了范围界定,对该领域的开创性评论进行了更新。我们描述了近期的研究结果是如何质疑或证实上皮细胞的经典观点的。除了综述之外,我们还记录了自1980年以来用于描述多纤毛上皮细胞的基本方法和研究特点。我们的综述为今后研究成熟的多纤毛上皮细胞提供了全面的资料。
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引用次数: 0
Integrated analyses reveal two molecularly and clinically distinct subtypes of H3 K27M-mutant diffuse midline gliomas with prognostic significance 综合分析揭示了H3 K27M突变弥漫中线胶质瘤的两种分子和临床不同亚型,具有预后意义
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-10 DOI: 10.1007/s00401-024-02800-3
Lotte Stegat, Alicia Eckhardt, Antonia Gocke, Sina Neyazi, Lara Pohl, Simone Schmid, Matthias Dottermusch, Stephan Frank, Hans Pinnschmidt, Jochen Herms, Markus Glatzel, Matija Snuderl, Leonille Schweizer, Christian Thomas, Julia Neumann, Mario M. Dorostkar, Ulrich Schüller, Annika K. Wefers

H3 K27M-altered diffuse midline gliomas (DMGs) are highly malignant tumours that arise in the midline structures of the CNS. Most DMGs carry an H3 K27M-mutation in one of the genes encoding for histone H3. Recent studies suggested that epigenetic subgroups of DMGs can be distinguished based on alterations in the MAPK-signalling pathway, tumour localisation, mutant H3-gene, or overall survival (OS). However, as these parameters were studied individually, it is unclear how they collectively influence survival. Hence, we analysed dependencies between different parameters, to define novel epigenetic, clinically meaningful subgroups of DMGs. We collected a multifaceted cohort of 149 H3 K27M-mutant DMGs, also incorporating data of published cases. DMGs were included in the study if they could be clearly allocated to the spinal cord (n = 31; one patient with an additional sellar tumour), medulla (n = 20), pons (n = 64) or thalamus (n = 33), irrespective of further known characteristics. We then performed global genome-wide DNA methylation profiling and, for a subset, DNA sequencing and survival analyses. Unsupervised hierarchical clustering of DNA methylation data indicated two clusters of DMGs, i.e. subtypes DMG-A and DMG-B. These subtypes differed in mutational spectrum, tumour localisation, age at diagnosis and overall survival. DMG-A was enriched for DMGs with MAPK-mutations, medullary localisation and adult age. 13% of DMG-A had a methylated MGMT promoter. Contrarily, DMG-B was enriched for cases with TP53-mutations, PDGFRA-amplifications, pontine localisation and paediatric patients. In univariate analyses, the features enriched in DMG-B were associated with a poorer survival. However, all significant parameters tested were dependent on the cluster attribution, which had the largest effect on survival: DMG-A had a significantly better survival compared to DMG-B (p < 0.001). Hence, the subtype attribution based on two methylation clusters can be used to predict survival as it integrates different molecular and clinical parameters.

H3 K27M变异弥漫性中线胶质瘤(DMGs)是一种发生在中枢神经系统中线结构的高度恶性肿瘤。大多数弥漫性中线胶质瘤的组蛋白H3编码基因之一携带H3 K27M突变。最近的研究表明,DMG 的表观遗传亚群可根据 MAPK 信号通路、肿瘤定位、突变 H3 基因或总生存期(OS)的改变加以区分。然而,由于这些参数是单独研究的,因此尚不清楚它们如何共同影响生存。因此,我们分析了不同参数之间的依赖关系,以确定新的具有临床意义的DMGs表观遗传亚组。我们收集了149例H3 K27M突变DMG的多方面队列,同时还纳入了已发表病例的数据。如果DMG可以明确归属于脊髓(31例;其中一名患者伴有额外的鞘膜肿瘤)、延髓(20例)、脑桥(64例)或丘脑(33例),则无论其他已知特征如何,均被纳入研究。然后,我们进行了全基因组DNA甲基化分析,并对部分患者进行了DNA测序和生存分析。DNA甲基化数据的无监督分层聚类显示,DMGs有两个聚类,即DMG-A和DMG-B亚型。这两个亚型在突变谱、肿瘤定位、确诊年龄和总生存率方面存在差异。DMG-A富含MAPK突变、髓质定位和成年年龄。13%的DMG-A具有甲基化的MGMT启动子。相反,DMG-B富集于TP53突变、PDGFRA扩增、桥脑定位和儿科患者。在单变量分析中,DMG-B富集的特征与较差的生存率有关。然而,所有测试的重要参数都取决于集群归因,而集群归因对生存率的影响最大:与 DMG-B 相比,DMG-A 的生存率明显更高(p <0.001)。因此,基于两个甲基化群的亚型归因可用于预测生存率,因为它整合了不同的分子和临床参数。
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引用次数: 0
Novel mutation of SMPX-related scapuloperoneal myopathy and myofibrillar myopathy 与 SMPX 相关的肩胛骨肌病和肌纤维肌病的新型变异。
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-04 DOI: 10.1007/s00401-024-02798-8
Zhenyu Li, Xujun Chu, Yize Li, Zhiying Xie, Meng Yu, Jianwen Deng, He Lv, Wei Zhang, Zhaoxia Wang, Yun Yuan, Lingchao Meng
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引用次数: 0
Rapid brain lymphoma diagnostics through nanopore sequencing of cytology-negative cerebrospinal fluid 通过对细胞学阴性脑脊液进行纳米孔测序快速诊断脑淋巴瘤。
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-03 DOI: 10.1007/s00401-024-02793-z
J. Hench, C. Hultschig, I. Bratic Hench, H. Sadasivan, Ö Yaldizli, G. Hutter, S. Dirnhofer, A. Tzankov, S. Frank
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引用次数: 0
Glioblastoma, IDH-wildtype with primarily leptomeningeal localization diagnosed by nanopore sequencing of cell-free DNA from cerebrospinal fluid 通过对脑脊液中的无细胞DNA进行纳米孔测序,诊断出主要位于脑膜外的IDH-野生型胶质母细胞瘤。
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-03 DOI: 10.1007/s00401-024-02792-0
Nik Sol, Evert-Jan Kooi, Marc Pagès-Gallego, Dieta Brandsma, Marianna Bugiani, Jeroen de Ridder, Pieter Wesseling, Carlo Vermeulen
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引用次数: 0
Association of quantitative histopathology measurements with antemortem medial temporal lobe cortical thickness in the Alzheimer’s disease continuum 定量组织病理学测量与阿尔茨海默氏症连续症中死前颞叶内侧皮质厚度的关联。
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-03 DOI: 10.1007/s00401-024-02789-9
Amanda E. Denning, Ranjit Ittyerah, Lisa M. Levorse, Niyousha Sadeghpour, Chinmayee Athalye, Eunice Chung, Sadhana Ravikumar, Mengjin Dong, Michael Tran Duong, Yue Li, Ademola Ilesanmi, Lasya P. Sreepada, Philip Sabatini, MaKayla Lowe, Alejandra Bahena, Jamila Zablah, Barbara E. Spencer, Ryohei Watanabe, Boram Kim, Maja Højvang Sørensen, Pulkit Khandelwal, Christopher Brown, Stanislau Hrybouski, Sharon X. Xie, Robin de Flores, John L. Robinson, Theresa Schuck, Daniel T. Ohm, Sanaz Arezoumandan, Sílvia Porta, John A. Detre, Ricardo Insausti, Laura E. M. Wisse, Sandhitsu R. Das, David J. Irwin, Edward B. Lee, David A. Wolk, Paul A. Yushkevich

The medial temporal lobe (MTL) is a hotspot for neuropathology, and measurements of MTL atrophy are often used as a biomarker for cognitive decline associated with neurodegenerative disease. Due to the aggregation of multiple proteinopathies in this region, the specific relationship of MTL atrophy to distinct neuropathologies is not well understood. Here, we develop two quantitative algorithms using deep learning to measure phosphorylated tau (p-tau) and TDP-43 (pTDP-43) pathology, which are both known to accumulate in the MTL and are associated with MTL neurodegeneration. We focus on these pathologies in the context of Alzheimer’s disease (AD) and limbic predominant age-related TDP-43 encephalopathy (LATE) and apply our deep learning algorithms to distinct histology sections, on which MTL subregions were digitally annotated. We demonstrate that both quantitative pathology measures show high agreement with expert visual ratings of pathology and discriminate well between pathology stages. In 140 cases with antemortem MR imaging, we compare the association of semi-quantitative and quantitative postmortem measures of these pathologies in the hippocampus with in vivo structural measures of the MTL and its subregions. We find widespread associations of p-tau pathology with MTL subregional structural measures, whereas pTDP-43 pathology had more limited associations with the hippocampus and entorhinal cortex. Quantitative measurements of p-tau pathology resulted in a significantly better model of antemortem structural measures than semi-quantitative ratings and showed strong associations with cortical thickness and volume. By providing a more granular measure of pathology, the quantitative p-tau measures also showed a significant negative association with structure in a severe AD subgroup where semi-quantitative ratings displayed a ceiling effect. Our findings demonstrate the advantages of using quantitative neuropathology to understand the relationship of pathology to structure, particularly for p-tau, and motivate the use of quantitative pathology measurements in future studies.

内侧颞叶(MTL)是神经病理学的热点区域,对MTL萎缩的测量通常被用作与神经退行性疾病相关的认知能力下降的生物标志物。由于该区域聚集了多种蛋白病,MTL萎缩与不同神经病理学的具体关系还不十分清楚。在这里,我们利用深度学习开发了两种定量算法来测量磷酸化 tau(p-tau)和 TDP-43(pTDP-43)的病理变化,已知这两种病理变化都会在 MTL 中聚集,并与 MTL 神经变性有关。我们重点研究了阿尔茨海默病(AD)和肢端占优势的年龄相关 TDP-43 脑病(LATE)的病理变化,并将深度学习算法应用于不同的组织学切片,在这些切片上对 MTL 亚区进行了数字注释。我们证明,这两种定量病理学测量方法与专家的病理学目测评级具有很高的一致性,并能很好地区分不同的病理学阶段。在 140 个有死前磁共振成像的病例中,我们比较了海马中这些病理变化的半定量和定量死后测量值与 MTL 及其亚区的活体结构测量值之间的关联。我们发现p-tau病变与MTL亚区域结构测量结果存在广泛关联,而pTDP-43病变与海马和内侧皮层的关联则较为有限。与半定量评分相比,p-tau病理的定量测量能更好地建立死前结构测量模型,并显示出与皮质厚度和体积的密切联系。通过提供更精细的病理测量结果,定量p-tau测量结果还显示,在半定量评分显示出天花板效应的严重AD亚组中,p-tau测量结果与结构呈显著负相关。我们的研究结果证明了使用定量神经病理学方法来了解病理学与结构之间关系的优势,尤其是p-tau,这也促使我们在未来的研究中使用定量病理学测量方法。
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引用次数: 0
Histopathologic correlates of opioid-associated injury in CHANTER syndrome: first report of a post-mortem examination 陈特综合征中阿片相关损伤的组织病理学相关性:首次尸检报告
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-31 DOI: 10.1007/s00401-024-02797-9
Katherine E. Schwetye, Lakshmi Ramachandran Nair, Joseph Boyle, Jed A. Barash

Opioid-associated brain injury may involve selective regions, including the hippocampi alone, globi pallidi, and cerebellar hemispheres. Opioid-associated amnestic syndrome, for example, is one clinical correlate of hippocampal injury as manifest by MRI abnormality. When all three regions are involved in what may be a more fulminant injury, the syndrome is termed “cerebellar, hippocampal, and basal nuclei transient edema with restricted diffusion (CHANTER)”, initially described in 2019. Until now, to our knowledge, there have been no histopathologic correlates to the imaging findings specifically in CHANTER syndrome. Here, for the first time, we present histopathologic findings of the post-mortem brain from a patient who died from complications of CHANTER syndrome following fentanyl intoxication. These observations included microhemorrhage, reactive and necrotic vasculature, eosinophilic neuronal necrosis, axonal swelling and spheroids, and frank infarction. The findings support previous experimental models implicating both hypoxic–ischemic and cytotoxic mechanisms in the tissue damage associated with CHANTER syndrome, though further work is needed to better characterize the exact cellular pathways involved to develop targeted treatments.

阿片类药物相关脑损伤可能涉及选择性区域,包括单纯海马、苍白球和小脑半球。例如,阿片相关失忆综合征就是海马损伤的一种临床表现,表现为核磁共振成像异常。当这三个区域都受累时,可能是一种更严重的损伤,这种综合征被称为 "小脑、海马和基底核一过性水肿伴弥散受限(CHANTER)",最初是在 2019 年描述的。据我们所知,迄今为止,CHANTER 综合征的影像学发现还没有组织病理学相关性。在此,我们首次展示了一名因芬太尼中毒后并发 CHANTER 综合征而死亡的患者的尸检脑组织病理学结果。这些观察结果包括微出血、反应性和坏死性血管、嗜酸性粒细胞性神经元坏死、轴突肿胀和球形体以及明显的梗死。这些研究结果支持以前的实验模型,即缺氧缺血和细胞毒性机制都与陈氏综合征的组织损伤有关,但还需要进一步研究,以更好地确定所涉及的确切细胞通路,从而开发出有针对性的治疗方法。
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引用次数: 0
Disability independent of cerebral white matter demyelination in progressive multiple sclerosis 进行性多发性硬化症患者的残疾与脑白质脱髓鞘无关
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-31 DOI: 10.1007/s00401-024-02796-w
Vikas Singh, Yufan Zheng, Daniel Ontaneda, Kedar R Mahajan, Jameson Holloman, Robert J Fox, Kunio Nakamura, Bruce D Trapp

The pathogenic mechanisms contributing to neurological disability in progressive multiple sclerosis (PMS) are poorly understood. Cortical neuronal loss independent of cerebral white matter (WM) demyelination in myelocortical MS (MCMS) and identification of MS patients with widespread cortical atrophy and disability progression independent of relapse activity (PIRA) support pathogenic mechanisms other than cerebral WM demyelination. The three-dimensional distribution and underlying pathology of myelinated T2 lesions were investigated in postmortem MCMS brains. Postmortem brain slices from previously characterized MCMS (10 cases) and typical MS (TMS) cases (12 cases) were co-registered with in situ postmortem T2 hyperintensities and T1 hypointensities. T1 intensity thresholds were used to establish a classifier that differentiates MCMS from TMS. The classifier was validated in 36 uncharacterized postmortem brains and applied to baseline MRIs from 255 living PMS participants enrolled in SPRINT-MS. Myelinated T2 hyperintensities in postmortem MCMS brains have a contiguous periventricular distribution that expands at the occipital poles of the lateral ventricles where a surface-in gradient of myelinated axonal degeneration was observed. The MRI classifier distinguished pathologically confirmed postmortem MCMS and TMS cases with an accuracy of 94%. For SPRINT-MS patients, the MRI classifier identified 78% as TMS, 10% as MCMS, and 12% with a paucity of cerebral T1 and T2 intensities. In SPRINT-MS, expanded disability status scale and brain atrophy measures were similar in MCMS and TMS cohorts. A paucity of cerebral WM demyelination in 22% of living PMS patients raises questions regarding a primary role for cerebral WM demyelination in disability progression in all MS patients and has implications for clinical management of MS patients and clinical trial outcomes in PMS. Periventricular myelinated fiber degeneration provides additional support for surface-in gradients of neurodegeneration in MS.

人们对导致进行性多发性硬化症(PMS)神经系统残疾的致病机制知之甚少。脊髓皮质多发性硬化症(MCMS)中独立于大脑白质(WM)脱髓鞘的皮质神经元缺失,以及具有广泛皮质萎缩和独立于复发活动(PIRA)的残疾进展的多发性硬化症患者的鉴定,都支持大脑WM脱髓鞘以外的致病机制。研究人员对多发性硬化症死后大脑中髓鞘化 T2 病变的三维分布和潜在病理进行了调查。对先前定性的 MCMS(10 例)和典型 MS(TMS)病例(12 例)的死后脑切片与原位死后 T2 高密度和 T1 低密度进行了共同登记。利用 T1 强度阈值建立了区分 MCMS 和 TMS 的分类器。该分类器在 36 个未定性的死后大脑中进行了验证,并应用于参加 SPRINT-MS 的 255 名在世 PMS 患者的基线 MRI。MCMS死后大脑中的髓质T2高密度呈连续的脑室周围分布,并在侧脑室枕极扩展,在该处观察到髓质轴突变性的由表及里梯度。核磁共振成像分类器能区分经病理证实的尸检MCMS和TMS病例,准确率高达94%。对于 SPRINT-MS 患者,核磁共振成像分类器将 78% 识别为 TMS,10% 识别为 MCMS,12% 识别为大脑 T1 和 T2 强度不足。在 SPRINT-MS 中,MCMS 和 TMS 组群的扩展残疾状况量表和脑萎缩测量结果相似。22%的在世多发性硬化症患者存在大脑WM脱髓鞘现象,这让人怀疑大脑WM脱髓鞘在所有多发性硬化症患者的残疾进展中是否起主要作用,并对多发性硬化症患者的临床管理和多发性硬化症的临床试验结果产生了影响。脑室周围髓鞘纤维变性为多发性硬化症神经退行性变的表里梯度提供了更多支持。
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引用次数: 0
PRDM16-DT is a novel lncRNA that regulates astrocyte function in Alzheimer’s disease PRDM16-DT 是一种新型 lncRNA,可调控阿尔茨海默病的星形胶质细胞功能
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-29 DOI: 10.1007/s00401-024-02787-x
Sophie Schröder, Ulrike Fuchs, Verena Gisa, Tonatiuh Pena, Dennis M. Krüger, Nina Hempel, Susanne Burkhardt, Gabriela Salinas, Anna-Lena Schütz, Ivana Delalle, Farahnaz Sananbenesi, Andre Fischer

Astrocytes provide crucial support for neurons, contributing to synaptogenesis, synaptic maintenance, and neurotransmitter recycling. Under pathological conditions, deregulation of astrocytes contributes to neurodegenerative diseases such as Alzheimer’s disease (AD). While most research in this field has focused on protein-coding genes, non-coding RNAs, particularly long non-coding RNAs (lncRNAs), have emerged as significant regulatory molecules. In this study, we identified the lncRNA PRDM16-DT as highly enriched in the human brain, where it is almost exclusively expressed in astrocytes. PRDM16-DT and its murine homolog, Prdm16os, are downregulated in the brains of AD patients and in AD models. In line with this, knockdown of PRDM16-DT and Prdm16os revealed its critical role in maintaining astrocyte homeostasis and supporting neuronal function by regulating genes essential for glutamate uptake, lactate release, and neuronal spine density through interactions with the RE1-Silencing Transcription factor (Rest) and Polycomb Repressive Complex 2 (PRC2). Notably, CRISPR-mediated overexpression of Prdm16os mitigated functional deficits in astrocytes induced by stimuli linked to AD pathogenesis. These findings underscore the importance of PRDM16-DT in astrocyte function and its potential as a novel therapeutic target for neurodegenerative disorders characterized by astrocyte dysfunction.

星形胶质细胞为神经元提供重要支持,有助于突触生成、突触维持和神经递质循环。在病理条件下,星形胶质细胞的失调会导致神经退行性疾病,如阿尔茨海默病(AD)。虽然这一领域的大部分研究都集中在蛋白编码基因上,但非编码 RNA,尤其是长非编码 RNA(lncRNA),已成为重要的调控分子。在这项研究中,我们发现了在人脑中高度富集的 lncRNA PRDM16-DT,它几乎只在星形胶质细胞中表达。PRDM16-DT及其鼠类同源物Prdm16os在AD患者和AD模型的大脑中下调。与此相一致,PRDM16-DT 和 Prdm16os 的敲除揭示了它在维持星形胶质细胞平衡和支持神经元功能方面的关键作用,它通过与 RE1-Silencing Transcription factor (Rest) 和 Polycomb Repressive Complex 2 (PRC2) 相互作用,调节谷氨酸摄取、乳酸释放和神经元脊柱密度所必需的基因。值得注意的是,CRISPR介导的Prdm16os过表达减轻了与AD发病机制相关的刺激诱导的星形胶质细胞的功能缺陷。这些发现强调了PRDM16-DT在星形胶质细胞功能中的重要性,以及其作为以星形胶质细胞功能障碍为特征的神经退行性疾病的新型治疗靶点的潜力。
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引用次数: 0
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Acta Neuropathologica
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