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Alpha-synuclein aggregates are phosphatase resistant. α-突触核蛋白聚集体对磷酸酶具有抗性。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-05-31 DOI: 10.1186/s40478-024-01785-0
S G Choi, T Tittle, D Garcia-Prada, J H Kordower, R Melki, B A Killinger

Alpha-synuclein (αsyn) is an intrinsically disordered protein that aggregates in the brain in several neurodegenerative diseases collectively called synucleinopathies. Phosphorylation of αsyn at serine 129 (PSER129) was considered rare in the healthy human brain but is enriched in pathological αsyn aggregates and is used as a specific marker for disease inclusions. However, recent observations challenge this assumption by demonstrating that PSER129 results from neuronal activity and can be readily detected in the non-diseased mammalian brain. Here, we investigated experimental conditions under which two distinct PSER129 pools, namely endogenous-PSER129 and aggregated-PSER129, could be detected and differentiated in the mammalian brain. Results showed that in the wild-type (WT) mouse brain, perfusion fixation conditions greatly influenced the detection of endogenous-PSER129, with endogenous-PSER129 being nearly undetectable after delayed perfusion fixation (30-min and 1-h postmortem interval). Exposure to anesthetics (e.g., Ketamine or xylazine) before perfusion did not significantly influence endogenous-PSER129 detection or levels. In situ, non-specific phosphatase calf alkaline phosphatase (CIAP) selectively dephosphorylated endogenous-PSER129 while αsyn preformed fibril (PFF)-seeded aggregates and genuine disease aggregates (Lewy pathology and Papp-Lantos bodies in Parkinson's disease and multiple systems atrophy brain, respectively) were resistant to CIAP-mediated dephosphorylation. The phosphatase resistance of aggregates was abolished by sample denaturation, and CIAP-resistant PSER129 was closely associated with proteinase K (PK)-resistant αsyn (i.e., a marker of aggregation). CIAP pretreatment allowed for highly specific detection of seeded αsyn aggregates in a mouse model that accumulates non-aggregated-PSER129. We conclude that αsyn aggregates are impervious to phosphatases, and CIAP pretreatment increases detection specificity for aggregated-PSER129, particularly in well-preserved biological samples (e.g., perfusion fixed or flash-frozen mammalian tissues) where there is a high probability of interference from endogenous-PSER129. Our findings have important implications for the mechanism of PSER129-accumulation in the synucleinopathy brain and provide a simple experimental method to differentiate endogenous-from aggregated PSER129.

α-突触核蛋白(αsyn)是一种内在紊乱的蛋白质,在几种统称为突触核蛋白病的神经退行性疾病中会在大脑中聚集。αsyn在丝氨酸129(PSER129)处的磷酸化在健康人脑中被认为是罕见的,但在病理αsyn聚集体中却富集,并被用作疾病内含物的特异性标记。然而,最近的观察结果挑战了这一假设,证明 PSER129 是神经元活动的结果,可在未患病的哺乳动物大脑中轻易检测到。在这里,我们研究了在哺乳动物大脑中检测和区分两种不同的 PSER129 池(即内源性 PSER129 和聚集性 PSER129)的实验条件。结果表明,在野生型(WT)小鼠脑中,灌注固定条件在很大程度上影响了内源性-PSER129的检测,延迟灌注固定(30分钟和1小时尸检间隔)后几乎检测不到内源性-PSER129。灌注前使用麻醉剂(如氯胺酮或甲苯噻嗪)不会显著影响内源性-PSER129的检测或水平。原位非特异性磷酸酶小牛碱性磷酸酶(CIAP)可选择性地使内源性-PSER129去磷酸化,而αsyn预成纤维蛋白(PFF)种子聚集体和真正的疾病聚集体(分别为帕金森病和多系统萎缩脑中的路易病理和帕普-兰托斯体)对CIAP介导的去磷酸化具有抗性。样品变性可消除聚集体的磷酸酶抗性,抗 CIAP 的 PSER129 与抗蛋白酶 K(PK)的 αsyn(即聚集体的标志物)密切相关。通过 CIAP 预处理,可以在积聚非聚集 PSER129 的小鼠模型中高度特异性地检测出种子αsyn 聚集。我们的结论是,αsyn 聚集体不受磷酸酶的影响,CIAP 预处理提高了聚集-PSER129 的检测特异性,尤其是在保存完好的生物样本(如灌注固定或急冻的哺乳动物组织)中,因为在这些样本中内源性-PSER129 的干扰概率很高。我们的发现对PSER129在突触核蛋白病大脑中的聚集机制具有重要意义,并提供了一种简单的实验方法来区分内源性和聚集性PSER129。
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引用次数: 0
Axonal autophagic vesicle transport in the rat optic nerve in vivo under normal conditions and during acute axonal degeneration 正常情况下和急性轴突变性期间体内大鼠视神经轴突自噬囊泡的运输
IF 7.1 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-05-29 DOI: 10.1186/s40478-024-01791-2
Xiaoyue Luo, Jiong Zhang, Johan Tolö, Sebastian Kügler, Uwe Michel, Mathias Bähr, Jan Christoph Koch
Neurons pose a particular challenge to degradative processes like autophagy due to their long and thin processes. Autophagic vesicles (AVs) are formed at the tip of the axon and transported back to the soma. This transport is essential since the final degradation of the vesicular content occurs only close to or in the soma. Here, we established an in vivo live-imaging model in the rat optic nerve using viral vector mediated LC3-labeling and two-photon-microscopy to analyze axonal transport of AVs. Under basal conditions in vivo, 50% of the AVs are moving with a majority of 85% being transported in the retrograde direction. Transport velocity is higher in the retrograde than in the anterograde direction. A crush lesion of the optic nerve results in a rapid breakdown of retrograde axonal transport while the anterograde transport stays intact over several hours. Close to the lesion site, the formation of AVs is upregulated within the first 6 h after crush, but the clearance of AVs and the levels of lysosomal markers in the adjacent axon are reduced. Expression of p150Glued, an adaptor protein of dynein, is significantly reduced after crush lesion. In vitro, fusion and colocalization of the lysosomal marker cathepsin D with AVs are reduced after axotomy. Taken together, we present here the first in vivo analysis of axonal AV transport in the mammalian CNS using live-imaging. We find that axotomy leads to severe defects of retrograde motility and a decreased clearance of AVs via the lysosomal system.
神经元由于其细长的过程,对自噬等降解过程构成了特别的挑战。自噬小泡(AV)在轴突顶端形成,并被运输回体细胞。这种运输是必不可少的,因为囊泡内容物的最终降解只发生在靠近轴突或轴突内的地方。在这里,我们利用病毒载体介导的 LC3 标记和双光子显微镜在大鼠视神经中建立了一个体内活体成像模型,以分析 AV 的轴突运输。在活体基础条件下,50% 的动眼神经在运动,其中 85% 的动眼神经逆行运输。逆行方向的运输速度高于顺行方向。视神经的挤压损伤会导致轴突逆行运输迅速中断,而顺行运输则在数小时内保持完好。在挤压后的最初 6 小时内,靠近病变部位的 AVs 形成速度加快,但邻近轴突中 AVs 的清除速度和溶酶体标记物的水平降低。挤压病变后,动力蛋白的适配蛋白p150Glued的表达明显减少。在体外,轴突切断术后溶酶体标志物 cathepsin D 与 AVs 的融合和共定位减少。综上所述,我们在此首次利用活体成像技术对哺乳动物中枢神经系统的轴突AV运输进行了体内分析。我们发现,轴突切断术会导致逆行性运动的严重缺陷以及通过溶酶体系统清除 AVs 的减少。
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引用次数: 0
The neuropathological landscape of small vessel disease and Lewy pathology in a cohort of Hispanic and non-Hispanic White decedents with Alzheimer disease. 西班牙裔和非西班牙裔白人阿尔茨海默氏症患者队列中的小血管疾病和路易病理的神经病理学特征。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-05-24 DOI: 10.1186/s40478-024-01773-4
Hsin-Pei Wang, Rebeca Scalco, Naomi Saito, Laurel Beckett, My-Le Nguyen, Emily Z Huie, Lawrence S Honig, Charles DeCarli, Robert A Rissman, Andrew F Teich, Dan M Mungas, Lee-Way Jin, Brittany N Dugger

Cerebrovascular and α-synuclein pathologies are frequently observed alongside Alzheimer disease (AD). The heterogeneity of AD necessitates comprehensive approaches to postmortem studies, including the representation of historically underrepresented ethnic groups. In this cohort study, we evaluated small vessel disease pathologies and α-synuclein deposits among Hispanic decedents (HD, n = 92) and non-Hispanic White decedents (NHWD, n = 184) from three Alzheimer's Disease Research Centers: Columbia University, University of California San Diego, and University of California Davis. The study included cases with a pathological diagnosis of Intermediate/High AD based on the National Institute on Aging- Alzheimer's Association (NIA-AA) and/or NIA-Reagan criteria. A 2:1 random comparison sample of NHWD was frequency-balanced and matched with HD by age and sex. An expert blinded to demographics and center origin evaluated arteriolosclerosis, cerebral amyloid angiopathy (CAA), and Lewy bodies/Lewy neurites (LBs/LNs) with a semi-quantitative approach using established criteria. There were many similarities and a few differences among groups. HD showed more severe Vonsattel grading of CAA in the cerebellum (p = 0.04), higher CAA density in the posterior hippocampus and cerebellum (ps = 0.01), and increased LBs/LNs density in the frontal (p = 0.01) and temporal cortices (p = 0.03), as determined by Wilcoxon's test. Ordinal logistic regression adjusting for age, sex, and center confirmed these findings except for LBs/LNs in the temporal cortex. Results indicate HD with AD exhibit greater CAA and α-synuclein burdens in select neuroanatomic regions when compared to age- and sex-matched NHWD with AD. These findings aid in the generalizability of concurrent arteriolosclerosis, CAA, and LBs/LNs topography and severity within the setting of pathologically confirmed AD, particularly in persons of Hispanic descent, showing many similarities and a few differences to those of NHW descent and providing insights into precision medicine approaches.

脑血管和α-突触核蛋白病变经常与阿尔茨海默病(AD)同时出现。由于阿尔茨海默病的异质性,有必要采用综合方法进行尸检研究,包括对历史上代表性不足的种族群体进行研究。在这项队列研究中,我们评估了三个阿尔茨海默病研究中心的西班牙裔死者(HD,n = 92)和非西班牙裔白人死者(NHWD,n = 184)的小血管疾病病理和α-突触核蛋白沉积:哥伦比亚大学、加州大学圣地亚哥分校和加州大学戴维斯分校。研究包括根据美国国家老龄化研究所-阿尔茨海默病协会(NIA-AA)和/或 NIA-Reagan 标准进行病理诊断的中度/高度 AD 病例。一个 2:1 的非老年痴呆症患者随机对比样本按年龄和性别与老年痴呆症患者进行了频率平衡和配对。一位对人口统计学和中心起源保密的专家采用既定标准,以半定量方法评估了动脉硬化、脑淀粉样血管病(CAA)和路易体/路易神经元(LBs/LNs)。各组之间存在许多相似之处和一些差异。经 Wilcoxon 检验,HD 患者小脑的 Vonsattel CAA 分级更严重(P = 0.04),后部海马和小脑的 CAA 密度更高(PS = 0.01),额叶(P = 0.01)和颞叶皮质的路易体/路易神经元密度更高(P = 0.03)。除颞叶皮层的 LBs/LNs 外,调整年龄、性别和中心的顺序逻辑回归证实了这些发现。结果表明,与年龄和性别匹配的NHWD患者相比,患有AD的HD患者在某些神经解剖区域表现出更大的CAA和α-突触核蛋白负担。这些发现有助于在病理确诊的AD患者中推广并发动脉硬化、CAA和LBs/LNs的地形和严重程度,特别是在西班牙裔患者中,显示出与NHW后裔的许多相似之处和一些不同之处,并为精准医疗方法提供了启示。
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引用次数: 0
Aberrant myonuclear domains and impaired myofiber contractility despite marked hypertrophy in MYMK-related, Carey-Fineman-Ziter Syndrome. 与 MYMK 相关的凯里-费内曼-齐特综合征尽管有明显的肥大,但肌核结构异常和肌纤维收缩能力受损。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-05-24 DOI: 10.1186/s40478-024-01783-2
Hannah F Dugdale, Yotam Levy, Heinz Jungbluth, Anders Oldfors, Julien Ochala

Carey Fineman Ziter Syndrome (CFZS) is a rare autosomal recessive disease caused by mutations in the MYMK locus which encodes the protein, myomaker. Myomaker is essential for fusion and concurrent myonuclei donation of muscle progenitors during growth and development. Strikingly, in humans, MYMK mutations appear to prompt myofiber hypertrophy but paradoxically, induce generalised muscle weakness. As the underlying cellular mechanisms remain unexplored, the present study aimed to gain insights by combining myofiber deep-phenotyping and proteomic profiling. Hence, we isolated individual muscle fibers from CFZS patients and performed mechanical, 3D morphological and proteomic analyses. Myofibers from CFZS patients were ~ 4x larger than controls and possessed ~ 2x more myonuclei than those from healthy subjects, leading to disproportionally larger myonuclear domain volumes. These greater myonuclear domain sizes were accompanied by smaller intrinsic cellular force generating-capacities in myofibers from CFZS patients than in control muscle cells. Our complementary proteomic analyses indicated remodelling in 233 proteins particularly those associated with cellular respiration. Overall, our findings suggest that myomaker is somewhat functional in CFZS patients, but the associated nuclear accretion may ultimately lead to non-functional hypertrophy and altered energy-related mechanisms in CFZS patients. All of these are likely contributors of the muscle weakness experienced by CFZS patients.

凯里-费恩曼-齐特综合征(CFZS)是一种罕见的常染色体隐性遗传病,由编码蛋白 Myomaker 的 MYMK 基因座突变引起。Myomaker 蛋白对于肌肉祖细胞在生长发育过程中的融合和同时捐献肌核至关重要。令人震惊的是,在人类中,MYMK 基因突变似乎会促使肌纤维肥大,但矛盾的是,它会诱发全身肌肉无力。由于潜在的细胞机制仍未探明,本研究旨在通过结合肌纤维深度分型和蛋白质组学分析来深入了解这一机制。因此,我们分离了 CFZS 患者的单个肌纤维,并进行了力学、三维形态学和蛋白质组分析。与健康人相比,CFZS 患者的肌纤维比对照组大约 4 倍,拥有的肌核比对照组多约 2 倍,导致肌核域体积不成比例地增大。与对照组肌肉细胞相比,CFZS 患者肌纤维的肌核结构域体积更大,但细胞内在的发力能力却更小。我们的补充蛋白质组分析表明,233 种蛋白质发生了重塑,尤其是那些与细胞呼吸相关的蛋白质。总之,我们的研究结果表明,CFZS 患者的肌生成器具有一定的功能,但相关的核增生最终可能导致 CFZS 患者出现无功能性肥大和能量相关机制的改变。所有这些都可能是导致 CFZS 患者肌无力的原因。
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引用次数: 0
Intravitreal MPTP drives retinal ganglion cell loss with oral nicotinamide treatment providing robust neuroprotection. 视网膜内 MPTP 会导致视网膜神经节细胞缺失,而口服烟酰胺可提供强有力的神经保护。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-05-21 DOI: 10.1186/s40478-024-01782-3
Anne Rombaut, Danica Jovancevic, Raymond Ching-Bong Wong, Alan Nicol, Rune Brautaset, David I Finkelstein, Christine T O Nguyen, James R Tribble, Pete A Williams

Neurodegenerative diseases have common underlying pathological mechanisms including progressive neuronal dysfunction, axonal and dendritic retraction, and mitochondrial dysfunction resulting in neuronal death. The retina is often affected in common neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Studies have demonstrated that the retina in patients with Parkinson's disease undergoes changes that parallel the dysfunction in the brain. These changes classically include decreased levels of dopamine, accumulation of alpha-synuclein in the brain and retina, and death of dopaminergic nigral neurons and retinal amacrine cells leading to gross neuronal loss. Exploring this disease's retinal phenotype and vision-related symptoms is an important window for elucidating its pathophysiology and progression, and identifying novel ways to diagnose and treat Parkinson's disease. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to model Parkinson's disease in animal models. MPTP is a neurotoxin converted to its toxic form by astrocytes, transported to neurons through the dopamine transporter, where it causes mitochondrial Complex I inhibition and neuron degeneration. Systemic administration of MPTP induces retinal changes in different animal models. In this study, we assessed the effects of MPTP on the retina directly via intravitreal injection in mice (5 mg/mL and 50 mg/mL to 7, 14 and 21 days post-injection). MPTP treatment induced the reduction of retinal ganglion cells-a sensitive neuron in the retina-at all time points investigated. This occurred without a concomitant loss of dopaminergic amacrine cells or neuroinflammation at any of the time points or concentrations tested. The observed neurodegeneration which initially affected retinal ganglion cells indicated that this method of MPTP administration could yield a fast and straightforward model of retinal ganglion cell neurodegeneration. To assess whether this model could be amenable to neuroprotection, mice were treated orally with nicotinamide (a nicotinamide adenine dinucleotide precursor) which has been demonstrated to be neuroprotective in several retinal ganglion cell injury models. Nicotinamide was strongly protective following intravitreal MPTP administration, further supporting intravitreal MPTP use as a model of retinal ganglion cell injury. As such, this model could be utilized for testing neuroprotective treatments in the context of Parkinson's disease and retinal ganglion cell injury.

神经退行性疾病具有共同的潜在病理机制,包括进行性神经元功能障碍、轴突和树突回缩,以及导致神经元死亡的线粒体功能障碍。帕金森病和阿尔茨海默病等常见的神经退行性疾病通常会影响视网膜。研究表明,帕金森病患者的视网膜会发生与大脑功能障碍相似的变化。这些变化通常包括多巴胺水平下降、α-突触核蛋白在大脑和视网膜中积聚、多巴胺能黑质神经元和视网膜杏仁核细胞死亡,从而导致神经元的严重缺失。探索这种疾病的视网膜表型和视力相关症状是阐明其病理生理学和进展的一个重要窗口,也是确定诊断和治疗帕金森病的新方法的一个重要窗口。1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)通常用于在动物模型中模拟帕金森病。MPTP 是一种神经毒素,由星形胶质细胞转化为毒性形式,通过多巴胺转运体转运到神经元,导致线粒体复合体 I 受抑制和神经元变性。在不同的动物模型中,MPTP 的全身给药会诱发视网膜变化。在本研究中,我们直接通过静脉注射(5 毫克/毫升和 50 毫克/毫升,注射后 7 天、14 天和 21 天)评估了 MPTP 对小鼠视网膜的影响。在所有调查时间点上,MPTP 处理都会导致视网膜神经节细胞(视网膜中的一种敏感神经元)减少。在测试的任何时间点或浓度下,都不会同时出现多巴胺能羊膜细胞的丢失或神经炎症。观察到的神经变性最初影响视网膜神经节细胞,这表明这种 MPTP 给药方法可以快速、直接地建立视网膜神经节细胞神经变性模型。为了评估这种模型是否可以用于神经保护,小鼠口服了烟酰胺(一种烟酰胺腺嘌呤二核苷酸前体)。尼古丁酰胺在玻璃体内注射 MPTP 后具有很强的保护作用,进一步支持将玻璃体内注射 MPTP 用作视网膜神经节细胞损伤模型。因此,该模型可用于测试帕金森病和视网膜神经节细胞损伤的神经保护疗法。
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引用次数: 0
Single-cell analysis of a progressive Rosai-Dorfman disease affecting the cerebral parenchyma: a case report. 影响大脑实质的进行性罗赛-多夫曼病的单细胞分析:病例报告。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-05-20 DOI: 10.1186/s40478-024-01794-z
Guo-Hao Huang, Guo-Long Liu, De-Zhi Huang, Xin-Wei Diao, Sheng-Qing Lv

Neurologic Rosai-Dorfman disease (RDD) is a rare type of non-Langerhans cell histiocytosis that affects the central nervous system. Most neurologic RDDs grow like meningiomas, have clear boundaries, and can be completely resected. However, a few RDDs are invasive and aggressive, and no effective treatment options are available because the molecular mechanisms involved remain unknown. Here, we report a case of deadly and glucocorticoid-resistant neurologic RDD and explore its possible pathogenic mechanisms via single-cell RNA sequencing. First, we identified two distinct but evolutionarily related histiocyte subpopulations (the C1Q+ and SPP1+ histiocytes) that accumulated in the biopsy sample. The expression of genes in the KRAS signaling pathway was upregulated, indicating gain-of-function of KRAS mutations. The C1Q+ and SPP1+ histiocytes were highly differentiated and arrested in the G1 phase, excluding the idea that RDD is a lympho-histio-proliferative disorder. Second, although C1Q+ histiocytes were the primary RDD cell type, SPP1+ histiocytes highly expressed several severe inflammation-related and invasive factors, such as WNT5A, IL-6, and MMP12, suggesting that SPP1+ histiocytes plays a central role in driving the progression of this disease. Third, oligodendrocytes were found to be the prominent cell type that initiates RDD via MIF and may resist glucocorticoid treatment via the MDK and PTN signaling pathways. In summary, in this case, we report a rare presentation of neurologic RDD and provided new insight into the pathogenic mechanisms of progressive neurologic RDD. This study will also offer evidence for developing precision therapies targeting this complex disease.

神经性罗赛-多夫曼病(RDD)是一种罕见的非朗格汉斯细胞组织细胞增生症,会影响中枢神经系统。大多数神经性罗赛-多夫曼病生长方式类似脑膜瘤,边界清晰,可以完全切除。然而,少数 RDDs 具有侵袭性和侵袭性,由于其分子机制尚不清楚,因此没有有效的治疗方案。在此,我们报告了一例致命的糖皮质激素耐药神经性 RDD,并通过单细胞 RNA 测序探讨了其可能的致病机制。首先,我们在活检样本中发现了两个不同但进化相关的组织细胞亚群(C1Q+ 和 SPP1+ 组织细胞)。KRAS信号通路中的基因表达上调,表明KRAS突变产生了功能增益。C1Q+ 和 SPP1+ 组织细胞高度分化并停滞在 G1 期,这排除了 RDD 是一种淋巴组织增生性疾病的可能性。其次,尽管C1Q+组织细胞是RDD的主要细胞类型,但SPP1+组织细胞高度表达多种严重炎症相关因子和侵袭因子,如WNT5A、IL-6和MMP12,这表明SPP1+组织细胞在推动该疾病进展方面起着核心作用。第三,研究发现少突胶质细胞是通过 MIF 启动 RDD 的主要细胞类型,并可通过 MDK 和 PTN 信号通路抵抗糖皮质激素治疗。总之,在本病例中,我们报告了一种罕见的神经系统 RDD 表现,并对进行性神经系统 RDD 的发病机制提供了新的见解。这项研究还将为开发针对这种复杂疾病的精准疗法提供证据。
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引用次数: 0
A longer time to relapse is associated with a larger increase in differences between paired primary and recurrent IDH wild-type glioblastomas at both the transcriptomic and genomic levels. 复发时间越长,配对的原发性和复发性IDH野生型胶质母细胞瘤在转录组和基因组水平上的差异就越大。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-05-18 DOI: 10.1186/s40478-024-01790-3
Wei-Min Ho, Chia-Ying Chen, Tai-Wei Chiang, Trees-Juen Chuang

Glioblastoma (GBM) is the most common malignant brain tumor in adults, which remains incurable and often recurs rapidly after initial therapy. While large efforts have been dedicated to uncover genomic/transcriptomic alternations associated with the recurrence of GBMs, the evolutionary trajectories of matched pairs of primary and recurrent (P-R) GBMs remain largely elusive. It remains challenging to identify genes associated with time to relapse (TTR) and construct a stable and effective prognostic model for predicting TTR of primary GBM patients. By integrating RNA-sequencing and genomic data from multiple datasets of patient-matched longitudinal GBMs of isocitrate dehydrogenase wild-type (IDH-wt), here we examined the associations of TTR with heterogeneities between paired P-R GBMs in gene expression profiles, tumor mutation burden (TMB), and microenvironment. Our results revealed a positive correlation between TTR and transcriptomic/genomic differences between paired P-R GBMs, higher percentages of non-mesenchymal-to-mesenchymal transition and mesenchymal subtype for patients with a short TTR than for those with a long TTR, a high correlation between paired P-R GBMs in gene expression profiles and TMB, and a negative correlation between the fitting level of such a paired P-R GBM correlation and TTR. According to these observations, we identified 55 TTR-associated genes and thereby constructed a seven-gene (ZSCAN10, SIGLEC14, GHRHR, TBX15, TAS2R1, CDKL1, and CD101) prognostic model for predicting TTR of primary IDH-wt GBM patients using univariate/multivariate Cox regression analyses. The risk scores estimated by the model were significantly negatively correlated with TTR in the training set and two independent testing sets. The model also segregated IDH-wt GBM patients into two groups with significantly divergent progression-free survival outcomes and showed promising performance for predicting 1-, 2-, and 3-year progression-free survival rates in all training and testing sets. Our findings provide new insights into the molecular understanding of GBM progression at recurrence and potential targets for therapeutic treatments.

胶质母细胞瘤(GBM)是成人中最常见的恶性脑肿瘤,至今仍无法治愈,而且往往在初次治疗后迅速复发。虽然人们一直在努力揭示与 GBM 复发相关的基因组/转录组变化,但配对的原发性和复发性(P-R)GBM 的进化轨迹在很大程度上仍然难以捉摸。要确定与复发时间(TTR)相关的基因并构建一个稳定有效的预后模型来预测原发性 GBM 患者的 TTR,仍然具有挑战性。通过整合多个数据集中与患者匹配的纵向异柠檬酸脱氢酶野生型(IDH-wt)GBM的RNA测序和基因组数据,我们在此研究了TTR与配对的P-R GBM在基因表达谱、肿瘤突变负荷(TMB)和微环境方面的异质性之间的关联。我们的结果显示,TTR 与配对 P-R GBM 之间的转录组/基因组差异呈正相关,短 TTR 患者的非间质向间质转化和间质亚型比例高于长 TTR 患者,配对 P-R GBM 的基因表达谱与 TMB 高度相关,而这种配对 P-R GBM 相关性的拟合水平与 TTR 呈负相关。根据这些观察结果,我们确定了 55 个 TTR 相关基因,并由此构建了一个七基因(ZSCAN10、SIGLEC14、GHRHR、TBX15、TAS2R1、CDKL1 和 CD101)预后模型,利用单变量/多变量 Cox 回归分析预测原发性 IDH-wt GBM 患者的 TTR。在训练集和两个独立测试集中,该模型估计的风险评分与TTR呈显著负相关。该模型还将 IDH-wt GBM 患者分为两组,这两组患者的无进展生存率有明显差异,在所有训练集和测试集中,该模型在预测 1 年、2 年和 3 年无进展生存率方面表现良好。我们的研究结果为了解 GBM 复发进展的分子机制和潜在的治疗目标提供了新的视角。
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引用次数: 0
Hyperoside mitigates photoreceptor degeneration in part by targeting cGAS and suppressing DNA-induced microglial activation. 金丝桃苷部分通过靶向cGAS和抑制DNA诱导的小胶质细胞活化来缓解感光细胞变性。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-05-16 DOI: 10.1186/s40478-024-01793-0
Daijin Li, Jie Chang, Yujue Wang, Xiaoye Du, Jing Xu, Jingang Cui, Teng Zhang, Yu Chen

Activated microglia play an important role in driving photoreceptor degeneration-associated neuroinflammation in the retina. Controlling pro-inflammatory activation of microglia holds promise for mitigating the progression of photoreceptor degeneration. Our previous study has demonstrated that pre-light damage treatment of hyperoside, a naturally occurring flavonol glycoside with antioxidant and anti-inflammatory activities, prevents photooxidative stress-induced photoreceptor degeneration and neuroinflammatory responses in the retina. However, the direct impact of hyperoside on microglia-mediated neuroinflammation during photoreceptor degeneration remains unknown. Upon verifying the anti-inflammatory effects of hyperoside in LPS-stimulated BV-2 cells, our results here further demonstrated that post-light damage hyperoside treatment mitigated the loss of photoreceptors and attenuated the functional decline of the retina. Meanwhile, post-light damage hyperoside treatment lowered neuroinflammatory responses and dampened microglial activation in the illuminated retinas. With respect to microglial activation, hyperoside mitigated the pro-inflammatory responses in DNA-stimulated BV-2 cells and lowered DNA-stimulated production of 2'3'-cGAMP in BV-2 cells. Moreover, hyperoside was shown to directly interact with cGAS and suppress the enzymatic activity of cGAS in a cell-free system. In conclusion, the current study suggests for the first time that the DNA sensor cGAS is a direct target of hyperoside. Hyperoside is effective at mitigating DNA-stimulated cGAS-mediated pro-inflammatory activation of microglia, which likely contributes to the therapeutic effects of hyperoside at curtailing neuroinflammation and alleviating neuroinflammation-instigated photoreceptor degeneration.

活化的小胶质细胞在驱动视网膜中与光感受器变性相关的神经炎症方面发挥着重要作用。控制小胶质细胞的促炎激活有望缓解感光器变性的进展。金丝桃苷是一种天然黄酮醇苷,具有抗氧化和抗炎活性,我们之前的研究表明,在光损伤前处理金丝桃苷可以防止光氧化应激诱导的视网膜感光器变性和神经炎症反应。然而,金丝桃苷对光感受器退化过程中小胶质细胞介导的神经炎症的直接影响仍然未知。在验证了金丝桃苷对 LPS 刺激的 BV-2 细胞的抗炎作用后,我们的研究结果进一步证明,光损伤后的金丝桃苷处理可减轻光感受器的损失,并减轻视网膜功能的衰退。同时,光损伤后的金丝桃苷处理降低了神经炎症反应,抑制了照明视网膜中的小胶质细胞活化。在小胶质细胞活化方面,金丝桃苷减轻了 DNA 刺激的 BV-2 细胞的促炎反应,并降低了 DNA 刺激的 BV-2 细胞中 2'3'-cGAMP 的产生。此外,在无细胞系统中,金丝桃苷还能与 cGAS 直接相互作用,抑制 cGAS 的酶活性。总之,目前的研究首次表明,DNA 传感器 cGAS 是金丝桃苷的直接靶标。金丝桃苷能有效减轻 DNA 刺激 cGAS 介导的小胶质细胞促炎激活,这可能有助于金丝桃苷在抑制神经炎症和减轻神经炎症诱发的感光细胞变性方面的治疗效果。
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引用次数: 0
Effects of local reduction of endogenous α-synuclein using antisense oligonucleotides on the fibril-induced propagation of pathology through the neural network in wild-type mice. 使用反义寡核苷酸局部减少内源性α-突触核蛋白对野生型小鼠神经网络中纤维诱导的病理学传播的影响
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-05-14 DOI: 10.1186/s40478-024-01766-3
Tatsuhiko Sano, Tetsuya Nagata, Satoe Ebihara, Kie Yoshida-Tanaka, Ayako Nakamura, Asuka Sasaki, Aki Shimozawa, Hideki Mochizuki, Toshiki Uchihara, Masato Hasegawa, Takanori Yokota

In Parkinson's disease and other synucleinopathies, fibrillar forms of α-synuclein (aSyn) are hypothesized to structurally convert and pathologize endogenous aSyn, which then propagates through the neural connections, forming Lewy pathologies and ultimately causing neurodegeneration. Inoculation of mouse-derived aSyn preformed fibrils (PFFs) into the unilateral striatum of wild-type mice causes widespread aSyn pathologies in the brain through the neural network. Here, we used the local injection of antisense oligonucleotides (ASOs) against Snca mRNA to confine the area of endogenous aSyn protein reduction and not to affect the PFFs properties in this model. We then varied the timing and location of ASOs injection to examine their impact on the initiation and propagation of aSyn pathologies in the whole brain and the therapeutic effect using abnormally-phosphorylated aSyn (pSyn) as an indicator. By injecting ASOs before or 0-14 days after the PFFs were inoculated into the same site in the left striatum, the reduction in endogenous aSyn in the striatum leads to the prevention and inhibition of the regional spread of pSyn pathologies to the whole brain including the contralateral right hemisphere. ASO post-injection inhibited extension from neuritic pathologies to somatic ones. Moreover, injection of ASOs into the right striatum prevented the remote regional spread of pSyn pathologies from the left striatum where PFFs were inoculated and no ASO treatment was conducted. This indicated that the reduction in endogenous aSyn protein levels at the propagation destination site can attenuate pSyn pathologies, even if those at the propagation initiation site are not inhibited, which is consistent with the original concept of prion-like propagation that endogenous aSyn is indispensable for this regional spread. Our results demonstrate the importance of recruiting endogenous aSyn in this neural network propagation model and indicate a possible potential for ASO treatment in synucleinopathies.

在帕金森病和其他突触核蛋白病中,α-突触核蛋白(aSyn)的纤维形式被假定为结构转换和病理化的内源性 aSyn,然后通过神经连接传播,形成路易病变并最终导致神经退行性变。在野生型小鼠的单侧纹状体中接种小鼠衍生的 aSyn 预成纤维(PFFs)会导致大脑神经网络中广泛的 aSyn 病变。在这里,我们利用局部注射针对 Snca mRNA 的反义寡核苷酸(ASO)来限制内源性 aSyn 蛋白减少的区域,而不影响该模型中 PFFs 的特性。然后,我们改变了注射 ASOs 的时间和位置,以异常磷酸化的 aSyn(pSyn)为指标,研究它们对全脑 aSyn 病变的启动和传播的影响以及治疗效果。通过在左侧纹状体同一部位接种 PFFs 之前或之后 0-14 天注射 ASO,减少纹状体中的内源性 aSyn,从而防止和抑制 pSyn 病变向包括对侧右半球在内的整个大脑的区域性扩散。ASO 注射后可抑制神经病变向躯体病变的扩展。此外,向右侧纹状体注射 ASO 还能阻止 pSyn 病变从接种了 PFF 但未进行 ASO 处理的左侧纹状体向远处区域扩散。这表明,即使不抑制传播起始点的内源性 aSyn 蛋白水平,也能降低传播目的地的内源性 aSyn 蛋白水平,这与朊病毒样传播的原始概念一致,即内源性 aSyn 对于这种区域性传播是不可或缺的。我们的研究结果证明了在这种神经网络传播模型中招募内源性 aSyn 的重要性,并指出了 ASO 治疗突触核蛋白病的可能潜力。
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引用次数: 0
Clinical implications of DNA methylation-based integrated classification of histologically defined grade 2 meningiomas. 基于 DNA 甲基化对组织学定义的 2 级脑膜瘤进行综合分类的临床意义。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-05-08 DOI: 10.1186/s40478-024-01739-6
Felix Ehret, Eilís Perez, Daniel Teichmann, Sandra Meier, Carola Geiler, Cosmas Zeus, Helene Franke, Siyer Roohani, David Wasilewski, Julia Onken, Peter Vajkoczy, Leonille Schweizer, David Kaul, David Capper

The combination of DNA methylation analysis with histopathological and genetic features allows for a more accurate risk stratification and classification of meningiomas. Nevertheless, the implications of this classification for patients with grade 2 meningiomas, a particularly heterogeneous tumor entity, are only partially understood. We correlate the outcomes of histopathologically confirmed grade 2 meningioma with an integrated molecular-morphologic risk stratification and determine its clinical implications. Grade 2 meningioma patients treated at our institution were re-classified using an integrated risk stratification involving DNA methylation array-based data, copy number assessment and TERT promoter mutation analyses. Grade 2 meningioma cases according to the WHO 2021 criteria treated between 2007 and 2021 (n = 100) were retrospectively analyzed. The median clinical and radiographic follow-up periods were 59.8 and 54.4 months. A total of 38 recurrences and 17 deaths were observed. The local control rates of the entire cohort after 2-, 4-, and 6-years were 84.3%, 68.5%, and 50.8%, with a median local control time of 77.2 months. The distribution of the integrated risk groups were as follows: 31 low, 54 intermediate, and 15 high risk cases. In the multivariable Cox regression analysis, integrated risk groups were significantly associated with the risk of local recurrence (hazard ratio (HR) intermediate: 9.91, HR high-risk: 7.29, p < 0.01). Gross total resections decreased the risk of local tumor progression (HR gross total resection: 0.19, p < 0.01). The comparison of 1p status and integrated risk groups (low vs. intermediate/high) revealed nearly identical local control rates within their respective subgroups. In summary, only around 50% of WHO 2021 grade 2 meningiomas have an intermediate risk profile. Integrated molecular risk stratification is crucial to guide the management of patients with grade 2 tumors and should be routinely applied to avoid over- and undertreatment, especially concerning the use of adjuvant radiotherapy.

DNA 甲基化分析与组织病理学和遗传学特征相结合,可对脑膜瘤进行更准确的风险分层和分类。然而,这种分类方法对 2 级脑膜瘤(一种异质性特别强的肿瘤实体)患者的影响只有部分了解。我们将组织病理学确诊的 2 级脑膜瘤的治疗结果与分子形态学综合风险分层法联系起来,并确定其临床意义。我院对接受治疗的2级脑膜瘤患者进行了综合风险分层,包括DNA甲基化阵列数据、拷贝数评估和TERT启动子突变分析。根据世界卫生组织2021年标准,对2007年至2021年间接受治疗的2级脑膜瘤病例(n = 100)进行了回顾性分析。临床和影像学随访时间的中位数分别为59.8个月和54.4个月。共观察到 38 例复发和 17 例死亡。整个组群在 2 年、4 年和 6 年后的局部控制率分别为 84.3%、68.5% 和 50.8%,中位局部控制时间为 77.2 个月。综合风险组的分布情况如下:低危 31 例,中危 54 例,高危 15 例。在多变量考克斯回归分析中,综合风险组与局部复发风险显著相关(中危比(HR):9.91;高危比(HR):9.91):9.91,HR 高危:7.29,P
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引用次数: 0
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Acta Neuropathologica Communications
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