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Nuclear pore and nucleocytoplasmic transport impairment in oxidative stress-induced neurodegeneration: relevance to molecular mechanisms in Pathogenesis of Parkinson’s and other related neurodegenerative diseases 氧化应激诱导的神经退行性病变中的核孔和核胞质转运损伤:与帕金森病和其他相关神经退行性疾病发病机制的分子机制有关
IF 15.1 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-23 DOI: 10.1186/s13024-024-00774-0
Zainab Riaz, Gabriel S. Richardson, Huajun Jin, Gary Zenitsky, Vellareddy Anantharam, Arthi Kanthasamy, Anumantha G. Kanthasamy
Nuclear pore complexes (NPCs) are embedded in the nuclear envelope and facilitate the exchange of macromolecules between the nucleus and cytoplasm in eukaryotic cells. The dysfunction of the NPC and nuclear transport plays a significant role in aging and the pathogenesis of various neurodegenerative diseases. Common features among these neurodegenerative diseases, including Parkinson’s disease (PD), encompass mitochondrial dysfunction, oxidative stress and the accumulation of insoluble protein aggregates in specific brain regions. The susceptibility of dopaminergic neurons to mitochondrial stress underscores the pivotal role of mitochondria in PD progression. Disruptions in mitochondrial-nuclear communication are exacerbated by aging and α-synuclein-induced oxidative stress in PD. The precise mechanisms underlying mitochondrial impairment-induced neurodegeneration in PD are still unclear. Evidence suggests that perturbations in dopaminergic neuronal nuclei are linked to PD-related neurodegeneration. These perturbations involve structural damage to the nuclear envelope and mislocalization of pivotal transcription factors, potentially driven by oxidative stress or α-synuclein pathology. The presence of protein aggregates, pathogenic mutations, and ongoing oxidative stress can exacerbate the dysfunction of NPCs, yet this mechanism remains understudied in the context of oxidative stress-induced PD. This review summarizes the link between mitochondrial dysfunction and dopaminergic neurodegeneration and outlines the current evidence for nuclear envelope and nuclear transport abnormalities in PD, particularly in oxidative stress. We highlight the potential role of nuclear pore and nucleocytoplasmic transport dysfunction in PD and stress the importance of systematically investigating NPC components in PD.
核孔复合体(NPC)嵌入核膜,促进真核细胞中细胞核与细胞质之间大分子的交换。NPC 和核转运功能障碍在衰老和各种神经退行性疾病的发病机制中起着重要作用。包括帕金森病(PD)在内的这些神经退行性疾病的共同特征包括线粒体功能障碍、氧化应激和特定脑区不溶性蛋白聚集体的积累。多巴胺能神经元易受线粒体压力的影响,这凸显了线粒体在帕金森病进展过程中的关键作用。在帕金森病中,衰老和α-突触核蛋白诱导的氧化应激加剧了线粒体-核交流的中断。线粒体损伤诱发帕金森病神经退行性变的确切机制尚不清楚。有证据表明,多巴胺能神经核的紊乱与帕金森病相关的神经变性有关。这些扰动涉及核包膜的结构性损伤和关键转录因子的错误定位,可能是由氧化应激或α-突触核蛋白病理学驱动的。蛋白聚集体、致病突变和持续氧化应激的存在会加剧 NPCs 的功能障碍,但这一机制在氧化应激诱导的帕金森病中仍未得到充分研究。本综述总结了线粒体功能障碍与多巴胺能神经退行性变之间的联系,并概述了目前在帕金森病中核包膜和核转运异常的证据,尤其是在氧化应激中。我们强调了核孔和核胞质转运功能障碍在帕金森病中的潜在作用,并强调了系统研究帕金森病中核包膜和核转运成分的重要性。
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引用次数: 0
Regulation of disease-associated microglia in the optic nerve by lipoxin B4 and ocular hypertension 脂质毒素 B4 和眼压对视神经中与疾病相关的小胶质细胞的调节作用
IF 15.1 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-20 DOI: 10.1186/s13024-024-00775-z
Shubham Maurya, Maggie Lin, Shruthi Karnam, Tanirika Singh, Matangi Kumar, Emily Ward, Jeremy Sivak, John G. Flanagan, Karsten Gronert
The resident astrocyte-retinal ganglion cell (RGC) lipoxin circuit is impaired during retinal stress, which includes ocular hypertension-induced neuropathy. Lipoxin B4 produced by homeostatic astrocytes directly acts on RGCs to increase survival and function in ocular hypertension-induced neuropathy. RGC death in the retina and axonal degeneration in the optic nerve are driven by the complex interactions between microglia and macroglia. Whether LXB4 neuroprotective actions include regulation of other cell types in the retina and/or optic nerve is an important knowledge gap. Cellular targets and signaling of LXB4 in the retina were defined by single-cell RNA sequencing. Retinal neurodegeneration was induced by injecting silicone oil into the anterior chamber of mouse eyes, which induced sustained and stable ocular hypertension. Morphological characterization of microglia populations in the retina and optic nerve was established by MorphOMICs and pseudotime trajectory analyses. The pathways and mechanisms of action of LXB4 in the optic nerve were investigated using bulk RNA sequencing. Transcriptomics data was validated by qPCR and immunohistochemistry. Differences between experimental groups were assessed by Student’s t-test and one-way ANOVA. Single-cell transcriptomics identified microglia as a primary target for LXB4 in the healthy retina. LXB4 downregulated genes that drive microglia environmental sensing and reactivity responses. Analysis of microglial function revealed that ocular hypertension induced distinct, temporally defined, and dynamic phenotypes in the retina and, unexpectedly, in the distal myelinated optic nerve. Microglial expression of CD74, a marker of disease-associated microglia in the brain, was only induced in a unique population of optic nerve microglia, but not in the retina. Genetic deletion of lipoxin formation correlated with the presence of a CD74 optic nerve microglia population in normotensive eyes, while LXB4 treatment during ocular hypertension shifted optic nerve microglia toward a homeostatic morphology and non-reactive state and downregulated the expression of CD74. Furthermore, we identified a correlation between CD74 and phospho-phosphoinositide 3-kinases (p-PI3K) expression levels in the optic nerve, which was reduced by LXB4 treatment. We identified early and dynamic changes in the microglia functional phenotype, reactivity, and induction of a unique CD74 microglia population in the distal optic nerve as key features of ocular hypertension-induced neurodegeneration. Our findings establish microglia regulation as a novel LXB4 target in the retina and optic nerve. LXB4 maintenance of a homeostatic optic nerve microglia phenotype and inhibition of a disease-associated phenotype are potential neuroprotective mechanisms for the resident LXB4 pathway.
在视网膜应激(包括眼压过高引起的神经病变)过程中,驻留星形胶质细胞-视网膜神经节细胞(RGC)脂毒素回路会受到损害。在眼压升高诱发的神经病变中,由同源性星形胶质细胞产生的脂质毒素 B4 可直接作用于 RGC,提高其存活率和功能。视网膜中 RGC 的死亡和视神经中轴突的变性是由小胶质细胞和大胶质细胞之间复杂的相互作用驱动的。LXB4的神经保护作用是否包括对视网膜和/或视神经中其他细胞类型的调节是一个重要的知识空白。通过单细胞 RNA 测序确定了 LXB4 在视网膜中的细胞靶点和信号传导。通过向小鼠眼球前房注射硅油诱导视网膜神经变性,从而诱导持续稳定的眼压升高。通过 MorphOMICs 和伪时间轨迹分析确定了视网膜和视神经中小胶质细胞群的形态特征。利用大容量 RNA 测序研究了 LXB4 在视神经中的作用途径和机制。转录组学数据通过 qPCR 和免疫组化进行验证。实验组之间的差异通过学生 t 检验和单因素方差分析进行评估。单细胞转录组学发现小胶质细胞是 LXB4 在健康视网膜中的主要作用靶点。LXB4 下调了驱动小胶质细胞环境感应和反应反应的基因。对小胶质细胞功能的分析表明,眼压过高会在视网膜中诱导出不同的、时间明确的动态表型,而且出乎意料的是,在远端有髓视神经中也是如此。CD74是大脑中与疾病相关的小胶质细胞的标志物,它只在视神经小胶质细胞的一个独特群体中被诱导表达,而在视网膜中却没有被诱导表达。在正常血压的眼睛中,脂质毒素形成的基因缺失与CD74视神经小胶质细胞群的存在相关,而在眼压过高期间,LXB4治疗会使视神经小胶质细胞转向平衡形态和非反应状态,并下调CD74的表达。此外,我们还发现了视神经中 CD74 与磷酸肌醇 3-激酶(p-PI3K)表达水平之间的相关性,LXB4 治疗可降低这种相关性。我们发现,小胶质细胞功能表型的早期动态变化、反应性以及远端视神经中独特的 CD74 小胶质细胞群的诱导是眼压诱导的神经变性的关键特征。我们的研究结果确立了小胶质细胞调控是 LXB4 在视网膜和视神经中的一个新靶点。LXB4 维持视神经小胶质细胞表型的平衡和抑制疾病相关表型是 LXB4 驻留途径的潜在神经保护机制。
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引用次数: 0
Stearoyl-CoA desaturase-1: a potential therapeutic target for neurological disorders 硬脂酰-CoA 去饱和酶-1:神经系统疾病的潜在治疗靶点
IF 15.1 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-19 DOI: 10.1186/s13024-024-00778-w
Melanie Loix, Sam Vanherle, Marta Turri, Stephan Kemp, Karl J. L. Fernandes, Jerome J. A. Hendriks, Jeroen F. J. Bogie
Disturbances in the fatty acid lipidome are increasingly recognized as key drivers in the progression of various brain disorders. In this review article, we delve into the impact of Δ9 fatty acid desaturases, with a particular focus on stearoyl-CoA desaturase-1 (SCD1), within the setting of neuroinflammation, neurodegeneration, and brain repair. Over the past years, it was established that inhibition or deficiency of SCD1 not only suppresses neuroinflammation but also protects against neurodegeneration in conditions such as multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease. This protective effect is achieved through different mechanisms including enhanced remyelination, reversal of synaptic and cognitive impairments, and mitigation of α-synuclein toxicity. Intriguingly, metabolic rerouting of fatty acids via SCD1 improves the pathology associated with X-linked adrenoleukodystrophy, suggesting context-dependent benign and harmful effects of SCD1 inhibition in the brain. Here, we summarize and discuss the cellular and molecular mechanisms underlying both the beneficial and detrimental effects of SCD1 in these neurological disorders. We explore commonalities and distinctions, shedding light on potential therapeutic challenges. Additionally, we touch upon future research directions that promise to deepen our understanding of SCD1 biology in brain disorders and potentially enhance the clinical utility of SCD1 inhibitors.
脂肪酸脂质体的紊乱越来越被认为是导致各种脑部疾病恶化的关键因素。在这篇综述文章中,我们将深入探讨Δ9脂肪酸去饱和酶,特别是硬脂酰-CoA去饱和酶-1(SCD1)在神经炎症、神经变性和脑修复中的影响。在过去的几年里,人们已经证实,抑制或缺乏 SCD1 不仅能抑制神经炎症,还能防止多发性硬化症、阿尔茨海默病和帕金森病等疾病的神经变性。这种保护作用是通过不同的机制实现的,包括增强髓鞘再形成、逆转突触和认知障碍以及减轻α-突触核蛋白毒性。耐人寻味的是,通过 SCD1 改变脂肪酸的代谢路线可以改善与 X 连锁肾上腺白质营养不良症相关的病理现象,这表明 SCD1 抑制作用对大脑的良性和有害影响是相互依赖的。在此,我们总结并讨论了 SCD1 在这些神经系统疾病中有益和有害作用的细胞和分子机制。我们探讨了共同点和不同点,揭示了潜在的治疗挑战。此外,我们还探讨了未来的研究方向,这些方向有望加深我们对 SCD1 在脑部疾病中生物学作用的理解,并有可能提高 SCD1 抑制剂的临床效用。
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引用次数: 0
Are oligodendrocytes the missing link in Alzheimer's disease and related dementia research? 少突胶质细胞是阿尔茨海默病和相关痴呆症研究中缺失的环节吗?
IF 14.9 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-17 DOI: 10.1186/s13024-024-00760-6
Sharyn L Rossi, Diane E Bovenkamp
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引用次数: 0
Contribution of amyloid deposition from oligodendrocytes in a mouse model of Alzheimer’s disease 阿尔茨海默病小鼠模型中少突胶质细胞淀粉样蛋白沉积的贡献
IF 15.1 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-16 DOI: 10.1186/s13024-024-00759-z
Akihiro Ishii, Joseph A. Pathoulas, Omar MoustafaFathy Omar, Yingying Ge, Annie Y. Yao, Tressa Pantalena, Neeraj Singh, John Zhou, Wanxia He, Patrick Murphy, Riqiang Yan, Xiangyou Hu
The accumulation of β-amyloid (Aβ) peptides into insoluble plaques is an early pathological feature of Alzheimer’s disease (AD). BACE1 is the sole β-secretase for Aβ generation, making it an attractive therapeutic target for AD therapy. While BACE1 inhibitors have been shown to reduce Aβ levels in people with AD, clinical trials targeting BACE1 have failed due to unwanted synaptic deficits. Understanding the physiological role of BACE1 in individual cell types is essential for developing effective BACE inhibitors for the treatment of AD. Recent single-cell RNA transcriptomic assays revealed that oligodendrocytes are enriched with genes required for generating Aβ. However, the contribution of oligodendrocytes to amyloid plaque burden in AD and the side effects of oligodendrocyte-specific Bace1 deletion remain to be explored. We generated an oligodendrocyte-specific Bace1 knockout model (Bace1fl/fl;Olig2-Cre) to monitor potential disruptions in myelination using standard electron microscopy. Long-term potentiation (LTP) was monitored to measure synaptic integrity. We crossed the Bace1fl/fl;Olig2-Cre model with heterozygous AppNL−G−F/wt knock-in AD mice to generate AD mice lacking oligodendrocyte Bace1 (Bace1fl/fl;Olig2-Cre; AppNL−G−F/wt) and examined amyloid plaque number and insoluble Aβ levels and gliosis in these animals. Single nuclei RNA sequencing experiments were conducted to examine molecular changes in response to Bace1 deficiency in oligodendrocytes in the wild type or APP knock-in background. Bace1 deletion in oligodendrocytes caused no change in myelin thickness in the corpus callosum but a marginal reduction in myelin sheath thickness of the optic nerve. Synaptic strength measured by LTP was not different between Bace1fl/fl;Olig2-Cre and age-matched Bace1fl/fl control animals, suggesting no major effect on synaptic plasticity. Intriguingly, deletion of Bace1 in 12-month-old heterozygous AD knock-in mice (Bace1fl/fl;Olig2-Cre; AppNL−G−F/wt mice) caused a significant reduction of amyloid plaques by ~ 33% in the hippocampus and ~ 29% in the cortex compared to age-matched AD mice (Bace1fl/fl;AppNL−G−F/wt). Insoluble Aβ1–40 and Aβ1–42 levels were reduced comparably while more astrocytes and microglia were observed in surrounding amyloid plaques. Unbiased single-nuclei RNA sequencing results revealed that deletion of oligodendrocyte Bace1 in APPNL−G−F/wt knock-in mice increased expression of genes associated with Aβ generation and clearance such as ADAM10, Ano4, ApoE, Il33, and Sort1. Our results provide compelling evidence that the amyloidogenic pathway in oligodendrocytes contributes to Aβ plaque formation in the AD brain. While specifically targeting BACE1 inhibition in oligodendrocytes for reducing Aβ pathology in AD is likely challenging, this is a potentially explorable strategy in future studies.
β淀粉样蛋白(Aβ)肽累积成不溶性斑块是阿尔茨海默病(AD)的早期病理特征。BACE1是生成Aβ的唯一β分泌酶,因此成为治疗阿尔茨海默病的一个有吸引力的治疗靶点。虽然 BACE1 抑制剂已被证明能降低注意力缺失症患者体内的 Aβ 水平,但针对 BACE1 的临床试验却因不必要的突触缺陷而失败。要开发出治疗AD的有效BACE抑制剂,了解BACE1在不同细胞类型中的生理作用至关重要。最近的单细胞 RNA 转录组测定显示,少突胶质细胞富含生成 Aβ 所需的基因。然而,少突胶质细胞对AD淀粉样斑块负担的贡献以及少突胶质细胞特异性Bace1缺失的副作用仍有待探索。我们建立了一种少突胶质细胞特异性 Bace1 基因敲除模型(Bace1fl/fl;Olig2-Cre),利用标准电子显微镜监测髓鞘化的潜在破坏。通过监测长期电位(LTP)来衡量突触的完整性。我们将Bace1fl/fl;Olig2-Cre模型与杂合子AppNL-G-F/wt基因敲入型AD小鼠杂交,产生了缺乏少突胶质细胞Bace1的AD小鼠(Bace1fl/fl;Olig2-Cre; AppNL-G-F/wt),并检测了这些动物体内的淀粉样斑块数量、不溶性Aβ水平和胶质细胞病变。研究人员进行了单核 RNA 测序实验,以检测野生型或 APP 基因敲入背景的少突胶质细胞中 Bace1 缺失所引起的分子变化。在少突胶质细胞中缺失 Bace1 不会导致胼胝体的髓鞘厚度发生变化,但会使视神经的髓鞘厚度略有减少。通过LTP测量的突触强度在Bace1fl/fl;Olig2-Cre和年龄匹配的Bace1fl/fl对照组动物之间没有差异,表明对突触可塑性没有重大影响。耐人寻味的是,与年龄匹配的 AD 小鼠(Bace1fl/fl;Olig2-Cre; AppNL-G-F/wt)相比,在 12 个月大的杂合子 AD 基因敲入小鼠(Bace1fl/fl;Olig2-Cre; AppNL-G-F/wt 小鼠)中删除 Bace1 可使海马中的淀粉样蛋白斑块显著减少约 33%,使皮层中的淀粉样蛋白斑块显著减少约 29%。不溶性 Aβ1-40 和 Aβ1-42 水平也相应降低,同时在淀粉样斑块周围观察到更多的星形胶质细胞和小胶质细胞。无偏见的单核 RNA 测序结果显示,APPNL-G-F/wt 基因敲入小鼠中少突胶质细胞 Bace1 的缺失增加了与 Aβ 生成和清除相关的基因的表达,如 ADAM10、Ano4、ApoE、Il33 和 Sort1。我们的研究结果提供了令人信服的证据,证明少突胶质细胞中的淀粉样蛋白生成途径有助于AD大脑中Aβ斑块的形成。虽然特异性地靶向抑制少突胶质细胞中的 BACE1 以减少 AD 中 Aβ 的病理变化可能具有挑战性,但这是未来研究中一个潜在的可探索的策略。
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引用次数: 0
CSF proteins of inflammation, proteolysis and lipid transport define preclinical AD and progression to AD dementia in cognitively unimpaired individuals 脑脊液中的炎症蛋白、蛋白分解蛋白和脂质转运蛋白可确定认知功能未受损个体的临床前注意力缺失症和注意力缺失性痴呆的进展情况
IF 15.1 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-11 DOI: 10.1186/s13024-024-00767-z
Marta del Campo, Carlos Quesada, Lisa Vermunt, Carel F. W. Peeters, Yanaika S. Hok-A-Hin, Calvin Trieu, Anouk den Braber, Inge M. W. Verberk, Pieter J. Visser, Betty M. Tijms, Wiesje M. van der Flier, Charlotte E. Teunissen
This preclinical AD CSF proteome study identified a panel of 12-CSF markers detecting amyloid positivity and clinical progression to AD with high accuracy; some of these CSF proteins related to immune function, neurotrophic processes, energy metabolism and endolysosomal functioning (e.g., ITGB2, CLEC5A, IGFBP-1, CST3) changed before amyloid positivity is established.
这项临床前AD CSF蛋白质组研究确定了一组12个CSF标记物,它们能高精度地检测淀粉样蛋白阳性和AD的临床进展;其中一些CSF蛋白质与免疫功能、神经营养过程、能量代谢和溶酶体内功能有关(如ITGB2、CLEC5A、IGFBP-1、CST3),它们在淀粉样蛋白阳性确立之前就发生了变化。
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引用次数: 0
Proteomic analysis of APOEε4 carriers implicates lipid metabolism, complement and lymphocyte signaling in cognitive resilience 对 APOEε4 携带者的蛋白质组分析表明,脂质代谢、补体和淋巴细胞信号传导与认知恢复能力有关
IF 15.1 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-31 DOI: 10.1186/s13024-024-00772-2
Keenan A. Walker, Yang An, Abhay Moghekar, Ruin Moaddel, Michael R. Duggan, Zhongsheng Peng, Qu Tian, Luke C. Pilling, Shannon M. Drouin, Mark A. Espeland, Stephen R Rapp, Kathleen M Hayden, Aladdin H. Shadyab, Ramon Casanova, Madhav Thambisetty, Peter R. Rapp, Dimitrios Kapogiannis, Luigi Ferrucci, Susan M. Resnick
Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease (AD). This case-cohort study used targeted plasma biomarkers and large-scale proteomics to examine the biological mechanisms that allow some APOEε4 carriers to maintain normal cognitive functioning in older adulthood. APOEε4 carriers and APOEε3 homozygotes enrolled in the Women’s Health Initiative Memory Study (WHIMS) from 1996 to 1999 were classified as resilient if they remained cognitively unimpaired beyond age 80, and as non-resilient if they developed cognitive impairment before or at age 80. AD pathology (Aß42/40) and neurodegeneration (NfL, tau) biomarkers, as well as 1007 proteins (Olink) were quantified in blood collected at study enrollment (on average 14 years prior) when participants were cognitively normal. We identified plasma proteins that distinguished between resilient and non-resilient APOEε4 carriers, examined whether these associations generalized to APOEε3 homozygotes, and replicated these findings in the UK Biobank. A total of 1610 participants were included (baseline age: 71.3 [3.8 SD] years; all White; 42% APOEε4 carriers). Compared to resilient APOEε4 carriers, non-resilient APOEε4 carriers had lower Aß42/40/tau ratio and greater NfL at baseline. Proteomic analyses identified four proteins differentially expressed between resilient and non-resilient APOEε4 carriers at an FDR-corrected P < 0.05. While one of the candidate proteins, a marker of neuronal injury (NfL), also distinguished resilient from non-resilient APOEε3 homozygotes, the other three proteins, known to be involved in lipid metabolism (ANGPTL4) and immune signaling (PTX3, NCR1), only predicted resilient vs. non-resilient status among APOEε4 carriers (protein*genotype interaction-P < 0.05). Three of these four proteins also predicted 14-year dementia risk among APOEε4 carriers in the UK Biobank validation sample (N = 9420). While the candidate proteins showed little to no association with targeted biomarkers of AD pathology, protein network and enrichment analyses suggested that natural killer (NK) cell and T lymphocyte signaling (via PKC-θ) distinguished resilient from non-resilient APOEε4 carriers. We identified and replicated a plasma proteomic signature associated with cognitive resilience among APOEε4 carriers. These proteins implicate specific immune processes in the preservation of cognitive status despite elevated genetic risk for AD. Future studies in diverse cohorts will be needed to assess the generalizability of these results.
载脂蛋白 E(APOE)ε4 等位基因是晚发性阿尔茨海默病(AD)的最强遗传风险因素。这项病例队列研究采用了靶向血浆生物标志物和大规模蛋白质组学方法,研究了使一些 APOEε4 携带者在老年期保持正常认知功能的生物机制。1996年至1999年参加妇女健康倡议记忆研究(WHIMS)的APOEε4携带者和APOEε3同卵双生者,如果在80岁以后仍无认知障碍,则被归类为有复原力者;如果在80岁以前或80岁时出现认知障碍,则被归类为无复原力者。我们对参与者在认知能力正常时(平均 14 年前)加入研究时采集的血液中的 AD 病理学(Aß42/40)和神经变性(NfL、tau)生物标志物以及 1007 种蛋白质(Olink)进行了量化。我们确定了区分有复原力和无复原力的 APOEε4 携带者的血浆蛋白,研究了这些关联是否会扩展到 APOEε3 同卵双生者,并在英国生物库中复制了这些发现。共纳入了 1610 名参与者(基线年龄:71.3 [3.8 SD] 岁;均为白人;42% 为 APOEε4 携带者)。与抗逆性 APOEε4 携带者相比,非抗逆性 APOEε4 携带者的 Aß42/40/tau 比值较低,基线 NfL 较高。蛋白质组学分析发现,抗逆性和非抗逆性 APOEε4 携带者之间有四种蛋白质的表达存在差异,FDR 校正后的 P < 0.05。其中一个候选蛋白是神经元损伤的标志物(NfL),它也能区分有复原力和无复原力的 APOEε3 基因携带者,而另外三个蛋白(已知参与脂质代谢(ANGPTL4)和免疫信号转导(PTX3、NCR1))仅能预测 APOEε4 基因携带者的复原力和无复原力状态(蛋白*基因型相互作用-P < 0.05)。在英国生物库验证样本(N = 9420)中,这四种蛋白质中有三种也能预测 APOEε4 携带者的 14 年痴呆风险。虽然候选蛋白质与AD病理学的靶向生物标志物几乎没有关联,但蛋白质网络和富集分析表明,自然杀伤(NK)细胞和T淋巴细胞信号传导(通过PKC-θ)可区分抗逆性APOEε4携带者和非抗逆性APOEε4携带者。我们发现并复制了与 APOEε4 携带者认知复原力相关的血浆蛋白质组特征。这些蛋白质表明,尽管AD遗传风险升高,但特定的免疫过程与认知状态的保持有关。未来需要在不同的队列中进行研究,以评估这些结果的普遍性。
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引用次数: 0
Repetitive transcranial magnetic stimulation alleviates motor impairment in Parkinson’s disease: association with peripheral inflammatory regulatory T-cells and SYT6 重复经颅磁刺激可减轻帕金森病的运动障碍:与外周炎性调节性 T 细胞和 SYT6 有关
IF 15.1 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-25 DOI: 10.1186/s13024-024-00770-4
Fen Xie, Bibiao Shen, Yuqi Luo, Hang Zhou, Zhenchao Xie, Shuzhen Zhu, Xiaobo Wei, Zihan Chang, Zhaohua Zhu, Changhai Ding, Kunlin Jin, Chengwu Yang, Lucia Batzu, K Ray Chaudhuri, Ling-Ling Chan, Eng-King Tan, Qing Wang
Repetitive transcranial magnetic stimulation (rTMS) has been used to treat various neurological disorders. However, the molecular mechanism underlying the therapeutic effect of rTMS on Parkinson’s disease (PD) has not been fully elucidated. Neuroinflammation like regulatory T-cells (Tregs) appears to be a key modulator of disease progression in PD. If rTMS affects the peripheral Tregs in PD remains unknown. Here, we conducted a prospective clinical study (Chinese ClinicalTrials. gov: ChiCTR 2100051140) involving 54 PD patients who received 10-day rTMS (10 Hz) stimulation on the primary motor cortex (M1) region or sham treatment. Clinical and function assessment as well as flow cytology study were undertaken in 54 PD patients who were consecutively recruited from the department of neurology at Zhujiang hospital between September 2021 and January 2022. Subsequently, we implemented flow cytometry analysis to examine the Tregs population in spleen of MPTP-induced PD mice that received rTMS or sham treatment, along with quantitative proteomic approach reveal novel molecular targets for Parkinson's disease, and finally, the RNA interference method verifies the role of these new molecular targets in the treatment of PD. We demonstrated that a 10-day rTMS treatment on the M1 motor cortex significantly improved motor dysfunction in PD patients. The beneficial effects persisted for up to 40 days, and were associated with an increase in peripheral Tregs. There was a positive correlation between Tregs and motor improvements in PD cases. Similarly, a 10-day rTMS treatment on the brains of MPTP-induced PD mice significantly ameliorated motor symptoms. rTMS reversed the downregulation of circulating Tregs and tyrosine hydroxylase neurons in these mice. It also increased anti-inflammatory mediators, deactivated microglia, and decreased inflammatory cytokines. These effects were blocked by administration of a Treg inhibitor anti-CD25 antibody in MPTP-induced PD mice. Quantitative proteomic analysis identified TLR4, TH, Slc6a3 and especially Syt6 as the hub node proteins related to Tregs and rTMS therapy. Lastly, we validated the role of Treg and rTMS-related protein syt6 in MPTP mice using the virus interference method. Our clinical and experimental studies suggest that rTMS improves motor function by modulating the function of Tregs and suppressing toxic neuroinflammation. Hub node proteins (especially Syt6) may be potential therapeutic targets. Chinese ClinicalTrials, ChiCTR2100051140. Registered 15 December 2021, https://www.chictr.org.cn/bin/project/edit?pid=133691 rTMS is a safe and non-invasive method for Parkinson's disease. In this study, we showed the proportion of CD4+CD25+CD127- regulatory T-cells (Tregs) in the peripheral blood was significantly increased after rTMS treatment. Similar effects of rTMS treatment were verified in MPTP-induced PD mice. Proteomic analysis and RNA interference analyses identified TLR4, TH, Slc6a3 and especially Syt6 as hub
重复经颅磁刺激(rTMS)已被用于治疗各种神经系统疾病。然而,经颅磁刺激治疗帕金森病(PD)的分子机制尚未完全阐明。调节性 T 细胞(Tregs)等神经炎症似乎是帕金森病疾病进展的一个关键调节因子。经颅磁刺激是否会影响帕金森病的外周Tregs仍是未知数。在此,我们进行了一项前瞻性临床研究(中国临床试验网:ChiCTR 2100051140),54名PD患者接受了为期10天的经颅磁刺激(10赫兹)或假治疗。我们对2021年9月至2022年1月期间从珠江医院神经内科连续招募的54名PD患者进行了临床和功能评估以及流式细胞学研究。随后,我们通过流式细胞术分析了接受经颅磁刺激或假治疗的MPTP诱导的帕金森病小鼠脾脏中的Tregs群体,并通过定量蛋白质组学方法揭示了帕金森病的新分子靶点,最后通过RNA干扰方法验证了这些新分子靶点在帕金森病治疗中的作用。我们证实,对 M1 运动皮层进行为期 10 天的经颅磁刺激治疗能显著改善帕金森病患者的运动功能障碍。这种益处可持续40天,并且与外周Tregs的增加有关。Tregs与运动功能改善之间存在正相关。同样,对多巴酚丁胺诱导的帕金森病小鼠大脑进行为期10天的经颅磁刺激治疗后,运动症状明显改善。经颅磁刺激还能增加抗炎介质、使小胶质细胞失活并减少炎性细胞因子。在 MPTP 诱导的帕金森病小鼠体内施用 Treg 抑制剂抗 CD25 抗体可阻断这些效应。定量蛋白质组分析发现,TLR4、TH、Slc6a3,尤其是 Syt6 是与 Tregs 和 rTMS 治疗相关的中枢节点蛋白。最后,我们利用病毒干扰法验证了 Treg 和 rTMS 相关蛋白 syt6 在 MPTP 小鼠中的作用。我们的临床和实验研究表明,经颅磁刺激通过调节Tregs的功能和抑制毒性神经炎症来改善运动功能。中枢节点蛋白(尤其是Syt6)可能是潜在的治疗靶点。中国临床试验网,ChiCTR2100051140。注册日期为2021年12月15日,https://www.chictr.org.cn/bin/project/edit?pid=133691 经颅磁刺激是治疗帕金森病的一种安全无创的方法。本研究显示,经颅磁刺激治疗后,外周血中CD4+CD25+CD127-调节性T细胞(Tregs)的比例显著增加。经颅磁刺激治疗在MPTP诱导的帕金森病小鼠中也验证了类似的效果。蛋白质组分析和RNA干扰分析发现,TLR4、TH、Slc6a3,尤其是Syt6是经颅磁刺激治疗可调节帕金森病的中枢节点蛋白。
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引用次数: 0
HDGFL2 cryptic protein: a portal to detection and diagnosis in neurodegenerative disease HDGFL2 隐匿蛋白:检测和诊断神经退行性疾病的入口
IF 15.1 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-25 DOI: 10.1186/s13024-024-00768-y
Ellen A. Albagli, Anna Calliari, Tania F. Gendron, Yong-Jie Zhang
<p>In 2006, TAR DNA-binding protein of 43 kDa (TDP-43) was discovered as the major ubiquitinated and aggregated protein in approximately 95% of amyotrophic lateral sclerosis (ALS) cases and 45% of frontotemporal lobar degeneration (FTLD) cases [1]. Since then, TDP-43 pathology has been identified in Alzheimer’s disease (AD), limbic-predominant age-related TDP-43 encephalopathy (LATE), and other neurodegenerative diseases [2]. This discovery initiated copious studies uncovering the pathomechanisms through which TDP-43, an RNA-binding protein with roles in alternative splicing, causes neurodegeneration [2] – chief among them, its loss of function owing to its aggregation in the cytoplasm and concurrent depletion from the nucleus.</p><p>TDP-43 proteinopathies share clinical, genetic, and pathological features, and this is particularly true of frontotemporal dementia (FTD) and ALS. While no treatments for FTD, ALS, or other TDP-43 proteinopathies yet exist, developing effective therapies for these fatal neurodegenerative diseases would benefit from biomarkers that facilitate an early and accurate diagnosis. Indeed, therapies are expected to be most effective when initiated early in the disease course. Biomarkers that identify the underlying pathology of patients with FTD in life would also aid in selecting appropriate participants for clinical trials targeting TDP-43 proteinopathy. As patients with behavioral variant FTD are essentially just as likely to develop TDP-43 or tau pathology, biomarkers that inform the presence of TDP-43 pathology would be particularly useful for this group, as would patients with AD who often develop mixed pathologies [3]. Although studies have examined whether TDP-43 itself could fulfill these biomarker needs, multiple efforts in detecting pathological TDP-43 species in biofluids have so far been unsuccessful [4]. Nevertheless, an exciting avenue being pursued harnesses the consequences of TDP-43 loss of function; more specifically, TDP-43’s inability to repress the splicing of non-conserved cryptic exons (CE) [5]. This engenders the production of novel RNA isoforms bearing non-conserved intronic sequences that often introduce frameshifts, premature stop codons, or premature polyadenylation sequences. For example, inclusion of a CE in <i>STMN2</i> mRNA produces a truncated stathmin-2 protein at the expense of its full-length counterpart, whereas inclusion of a CE in <i>UNC13A</i> mRNA reduces UNC13A protein expression (Fig. 1A) [6]. While cryptic RNAs including <i>STMN2</i>-CE and <i>UNC13A</i>-CE have been detected in postmortem brain tissue [6], they have yet to be detected in biofluids, hindering their application for biomarker development. Perhaps most pertinent to biomarker development, consequently, are the cryptic transcripts that generate <i>de novo</i> proteins.</p><figure><figcaption><b data-test="figure-caption-text">Fig. 1</b></figcaption><picture><source srcset="//media.springernature.com/lw685/springer-stat
随着我们进一步研究 HDGLF2-CE 作为生物标志物的作用,HDGFL2-CE 和其他隐性蛋白的功能也应得到阐明。Seddighi等人发现,HDGFL2-CE改变了HDGFL2的相互作用组,HDGFL2-CE与RNA结合蛋白的相互作用增加,而与细胞骨架蛋白的相互作用减少,这表明HDGFL2-CE诱导毒性增益和功能缺失,从而可能影响疾病的发生和发展[7]。破译转录本中隐性外显子内含物导致神经退行性变的病理机制将拓宽我们对疾病发病机制的认识,并可能为治疗 TDP-43 蛋白病提供更有针对性的方法。AD:阿尔茨海默病ALS:肌萎缩侧索硬化症CE:隐性外显子CNS:中枢神经系统CSF:脑脊液FTD:额颞叶痴呆FTLD:额颞叶变性HDGFL2:肝瘤衍生生长因子iPSC:诱导多能干细胞LATE:Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al.前颞叶变性和肌萎缩侧索硬化症中的泛素化 TDP-43。科学。2006;314(5796):130-3.Article CAS PubMed Google Scholar de Boer EMJ, Orie VK, Williams T, Baker MR, De Oliveira HM, Polvikoski T, et al. TDP-43 proteinopathies: a new wave of neurodegenerative diseases.J Neurol Neurosurg Psychiatry.2020;92(1):86-95.Article PubMed Google Scholar James BD, Wilson RS, Boyle PA, Trojanowski JQ, Bennett DA, Schneider JA.TDP-43阶段、混合病理和临床阿尔茨海默型痴呆。脑。2016;139(11):2983-93.Article PubMed Google Scholar Irwin KE, Sheth U, Wong PC, Gendron TF.肌萎缩侧索硬化症的体液生物标志物:综述。Mol Neurodegener.2024;19(1):9.Article PubMed Google Scholar Ling JP, Pletnikova O, Troncoso JC, Wong PC.TDP-43对非保守隐性外显子的抑制在ALS-FTD中受损。Science.2015;349(6248):650-5.Article CAS PubMed Google Scholar Mehta PR, Brown AL, Ward ME, Fratta P. The era of cryptic exons: implications for ALS-FTD.Mol Neurodegener.2023;18(1):16.Article CAS PubMed Google Scholar Seddighi S, Qi YA, Brown A-L, Wilkins OG, Bereda C, Belair C, et al. Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.Sci Transl Med.2024;16(734):eadg7162.Article CAS PubMed Google Scholar Irwin KE, Jasin P, Braunstein KE, Sinha IR, Garret MA, Bowden KD et al. A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS-FTD.Nat Med.2024:1-12.Calliari A, Daughrity LM, Albagli EA, Castellanos Otero P, Yue M, Jansen-West K, et al. HDGFL2隐性蛋白报告了神经退行性疾病中TDP-43病理的存在。Mol Neurodegeneration.2024;19(1):29.Article CAS Google Scholar Feng W, Beer JC, Hao Q, Ariyapala IS, Sahajan A, Komarov A, et al. NULISA: a proteomic liquid biopsy platform with attomolar sensitivity and high multiplexing.Nat Commun.2023;14(1):7238.Article CAS PubMed Google Scholar Britson KA, Ling JP, Braunstein KE, Montagne JM, Kastenschmidt JM, Wilson A, et al. 散发性包涵体肌炎异种移植模型中 T 细胞耗竭后 TDP-43 功能丧失和边缘空泡持续存在。Sci Transl Med.2022;14(628):eabi9196.Article CAS PubMed Google Scholar Estades Ayuso V, Pickles S, Todd T, Yue M, Jansen-West K, Song Y, et al. TDP-43-regulated cryptic RNAs accumulate in Alzheimer's disease brains.Mol Neurodegeneration.2023;18(1):57.Article CAS Google Scholar Agra Almeida Quadros AR, Li Z, Wang X, Ndayambaje IS, Aryal S, Ramesh N, et al. Cryptic splicing of stathmin-2 and UNC13A mRNAs is a pathological hallmark of TDP-43-associated Alzheimer's disease.Acta Neuropathol.2024;147(1):9.Article CAS PubMed Google Scholar Chung M, Carter EK, Veire AM, Dammer EB, Chang J, Duong DM, et al. Cryptic exon inclusion is a molecular signature of LATE-NC in aging brains.Acta Neuropathol.2024;147(1):29.Article CAS PubMed Google Scholar Download references作者得到了目标 ALS 基金会(Y.-J
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引用次数: 0
Gut-first Parkinson’s disease is encoded by gut dysbiome 帕金森病先发于肠道,是由肠道菌群失调造成的
IF 15.1 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-24 DOI: 10.1186/s13024-024-00766-0
Mário F. Munoz-Pinto, Emanuel Candeias, Inês Melo-Marques, A. Raquel Esteves, Ana Maranha, João D. Magalhães, Diogo Reis Carneiro, Mariana Sant’Anna, A. Raquel Pereira-Santos, António E Abreu, Daniela Nunes-Costa, Susana Alarico, Igor Tiago, Ana Morgadinho, João Lemos, Pedro N. Figueiredo, Cristina Januário, Nuno Empadinhas, Sandra Morais Cardoso
In Parkinson's patients, intestinal dysbiosis can occur years before clinical diagnosis, implicating the gut and its microbiota in the disease. Recent evidence suggests the gut microbiota may trigger body-first Parkinson Disease (PD), yet the underlying mechanisms remain unclear. This study aims to elucidate how a dysbiotic microbiome through intestinal immune alterations triggers PD-related neurodegeneration. To determine the impact of gut dysbiosis on the development and progression of PD pathology, wild-type male C57BL/6 mice were transplanted with fecal material from PD patients and age-matched healthy donors to challenge the gut-immune-brain axis. This study demonstrates that patient-derived intestinal microbiota caused midbrain tyrosine hydroxylase positive (TH +) cell loss and motor dysfunction. Ileum-associated microbiota remodeling correlates with a decrease in Th17 homeostatic cells. This event led to an increase in gut inflammation and intestinal barrier disruption. In this regard, we found a decrease in CD4 + cells and an increase in pro-inflammatory cytokines in the blood of PD transplanted mice that could contribute to an increase in the permeabilization of the blood–brain-barrier, observed by an increase in mesencephalic Ig-G-positive microvascular leaks and by an increase of mesencephalic IL-17 levels, compatible with systemic inflammation. Furthermore, alpha-synuclein aggregates can spread caudo-rostrally, causing fragmentation of neuronal mitochondria. This mitochondrial damage subsequently activates innate immune responses in neurons and triggers microglial activation. We propose that the dysbiotic gut microbiome (dysbiome) in PD can disrupt a healthy microbiome and Th17 homeostatic immunity in the ileum mucosa, leading to a cascade effect that propagates to the brain, ultimately contributing to PD pathophysiology. Our landmark study has successfully identified new peripheral biomarkers that could be used to develop highly effective strategies to prevent the progression of PD into the brain.
在帕金森病患者中,肠道菌群失调可能在临床诊断前数年就已发生,这说明肠道及其微生物群与帕金森病有关。最近的证据表明,肠道微生物群可能会诱发帕金森病(PD),但其潜在机制仍不清楚。本研究旨在阐明肠道免疫改变导致的微生物群失调如何引发帕金森病相关神经变性。为了确定肠道菌群失调对帕金森病病理发展和进展的影响,研究人员给野生型雄性 C57BL/6 小鼠移植了帕金森病患者和年龄匹配的健康供体的粪便,以挑战肠道-免疫-脑轴。这项研究表明,来自患者的肠道微生物群会导致中脑酪氨酸羟化酶阳性(TH +)细胞丢失和运动功能障碍。回肠相关微生物群的重塑与 Th17 平衡细胞的减少有关。这一事件导致肠道炎症和肠屏障破坏增加。在这方面,我们发现骨髓增生性疾病移植小鼠血液中 CD4 + 细胞减少,促炎症细胞因子增加,这可能导致血脑屏障通透性增加,表现为间脑 Ig-G 阳性微血管渗漏增加,间脑 IL-17 水平升高,这与全身炎症相符。此外,α-突触核蛋白聚集体可向尾骶部扩散,导致神经元线粒体碎裂。这种线粒体损伤随后会激活神经元的先天性免疫反应,并引发小胶质细胞活化。我们认为,帕金森病患者肠道微生物组(dysbiome)的失调会破坏回肠粘膜中健康的微生物组和 Th17 平衡免疫,导致向大脑传播的级联效应,最终导致帕金森病的病理生理学。我们这项具有里程碑意义的研究成功鉴定了新的外周生物标志物,这些标志物可用于开发高效策略,防止帕金森病向大脑发展。
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Molecular Neurodegeneration
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