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Regulated cell death in neurodegeneration: pathways and therapeutic horizons 神经变性中的调控细胞死亡:途径与治疗前景
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-24 DOI: 10.1007/s00401-024-02808-9
Dietmar Rudolf Thal, Bart De Strooper
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引用次数: 0
Tau accumulation is cleared by the induced expression of VCP via autophagy 诱导表达的 VCP 可通过自噬清除 Tau 的积累。
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-24 DOI: 10.1007/s00401-024-02804-z
Hoi-Khoanh Giong, Seung Jae Hyeon, Jae-Geun Lee, Hyun-Ju Cho, Uiyeol Park, Thor D. Stein, Junghee Lee, Kweon Yu, Hoon Ryu, Jeong-Soo Lee

Tauopathy, including frontotemporal lobar dementia and Alzheimer’s disease, describes a class of neurodegenerative diseases characterized by the aberrant accumulation of Tau protein due to defects in proteostasis. Upon generating and characterizing a stable transgenic zebrafish that expresses the human TAUP301L mutant in a neuron-specific manner, we found that accumulating Tau protein was efficiently cleared via an enhanced autophagy activity despite constant Tau mRNA expression; apparent tauopathy-like phenotypes were revealed only when the autophagy was genetically or chemically inhibited. We performed RNA-seq analysis, genetic knockdown, and rescue experiments with clinically relevant point mutations of valosin-containing protein (VCP), and showed that induced expression of VCP, an essential cytosolic chaperone for the protein quality system, was a key factor for Tau degradation via its facilitation of the autophagy flux. This novel function of VCP in Tau clearance was further confirmed in a tauopathy mouse model where VCP overexpression significantly decreased the level of phosphorylated and oligomeric/aggregate Tau and rescued Tau-induced cognitive behavioral phenotypes, which were reversed when the autophagy was blocked. Importantly, VCP expression in the brains of human Alzheimer’s disease patients was severely downregulated, consistent with its proposed role in Tau clearance. Taken together, these results suggest that enhancing the expression and activity of VCP in a spatiotemporal manner to facilitate the autophagy pathway is a potential therapeutic approach for treating tauopathy.

Tau病(包括额颞叶痴呆症和阿尔茨海默病)是一类神经退行性疾病,其特征是由于蛋白稳态缺陷导致的Tau蛋白异常积累。我们发现,尽管Tau mRNA的表达量保持不变,但积聚的Tau蛋白可通过增强的自噬活性被有效清除;只有当自噬受到遗传或化学抑制时,才会出现明显的类似Tau病的表型。我们对含缬氨酸蛋白(VCP)进行了RNA-seq分析、基因敲除以及与临床相关的点突变拯救实验,结果表明,VCP是蛋白质质量系统的重要细胞膜伴侣,其诱导表达是通过促进自噬通量降解Tau的关键因素。VCP在Tau清除中的这一新功能在tau病小鼠模型中得到了进一步证实,过量表达VCP可显著降低磷酸化Tau和寡聚/聚集Tau的水平,并挽救Tau诱导的认知行为表型。重要的是,VCP 在人类阿尔茨海默病患者大脑中的表达严重下调,这与它在 Tau 清除中的作用一致。综上所述,这些结果表明,以时空方式增强VCP的表达和活性以促进自噬途径是治疗牛头蛋白病的一种潜在治疗方法。
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引用次数: 0
TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition TDP-43通过抑制ATG4B隐性剪接调节神经组织中的LC3酰化
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-21 DOI: 10.1007/s00401-024-02780-4
Pascual Torres, Santiago Rico-Rios, Miriam Ceron-Codorniu, Marta Santacreu-Vilaseca, David Seoane-Miraz, Yahya Jad, Victòria Ayala, Guillermo Mariño, Maria Beltran, Maria P. Miralles, Pol Andrés-Benito, Joaquin Fernandez-Irigoyen, Enrique Santamaria, Carlos López-Otín, Rosa M. Soler, Monica Povedano, Isidro Ferrer, Reinald Pamplona, Matthew J. A. Wood, Miguel A. Varela, Manuel Portero-Otin

Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease with a mean survival time of three years. The 97% of the cases have TDP-43 nuclear depletion and cytoplasmic aggregation in motor neurons. TDP-43 prevents non-conserved cryptic exon splicing in certain genes, maintaining transcript stability, including ATG4B, which is crucial for autophagosome maturation and Microtubule-associated proteins 1A/1B light chain 3B (LC3B) homeostasis. In ALS mice (G93A), Atg4b depletion worsens survival rates and autophagy function. For the first time, we observed an elevation of LC3ylation in the CNS of both ALS patients and atg4b−/− mouse spinal cords. Furthermore, LC3ylation modulates the distribution of ATG3 across membrane compartments. Antisense oligonucleotides (ASOs) targeting cryptic exon restore ATG4B mRNA in TARDBP knockdown cells. We further developed multi-target ASOs targeting TDP-43 binding sequences for a broader effect. Importantly, our ASO based in peptide-PMO conjugates show brain distribution post-IV administration, offering a non-invasive ASO-based treatment avenue for neurodegenerative diseases.

肌萎缩侧索硬化症(ALS)是一种成人发病的运动神经元疾病,平均存活时间为三年。97%的病例在运动神经元中出现 TDP-43 核耗竭和胞质聚集。TDP-43 可阻止某些基因的非保守隐性外显子剪接,维持转录本的稳定性,其中包括对自噬体成熟和微管相关蛋白 1A/1B 轻链 3B(LC3B)平衡至关重要的 ATG4B。在 ALS 小鼠(G93A)中,Atg4b 的消耗会使存活率和自噬功能恶化。我们首次在 ALS 患者和 atg4b-/- 小鼠脊髓的中枢神经系统中观察到 LC3ylation 的升高。此外,LC3ylation 还能调节 ATG3 在膜区的分布。靶向隐性外显子的反义寡核苷酸(ASO)可恢复 TARDBP 敲除细胞中的 ATG4B mRNA。我们进一步开发了针对 TDP-43 结合序列的多靶点 ASO,以获得更广泛的效果。重要的是,我们基于多肽-PMO共轭物的ASO在静脉注射后显示出脑分布,为神经退行性疾病提供了一种基于ASO的非侵入性治疗途径。
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引用次数: 0
Association of in vivo retention of [18f] flortaucipir pet with tau neuropathology in corresponding brain regions [18f]氟陶西哌 pet 的体内滞留与相应脑区 tau 神经病理学的关系
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-19 DOI: 10.1007/s00401-024-02801-2
Tove Freiburghaus, Daria Pawlik, Kevin Oliveira Hauer, Rik Ossenkoppele, Olof Strandberg, Antoine Leuzy, Jonathan Rittmo, Cécilia Tremblay, Geidy E. Serrano, Michael J. Pontecorvo, Thomas G. Beach, Ruben Smith, Oskar Hansson

[18F]Flortaucipir is an FDA-approved tau-PET tracer that is increasingly utilized in clinical settings for the diagnosis of Alzheimer’s disease. Still, a large-scale comparison of the in vivo PET uptake to quantitative post-mortem tau pathology and to other co-pathologies is lacking. Here, we examined the correlation between in vivo [18F]flortaucipir PET uptake and quantitative post-mortem tau pathology in corresponding brain regions from the AVID A16 end-of-life study (n = 63). All participants underwent [18F]flortaucipir PET scans prior to death, followed by a detailed post-mortem neuropathological examination using AT8 (tau) immunohistochemistry. Correlations between [18F]flortaucipir standardized uptake value ratios (SUVRs) and AT8 immunohistochemistry were assessed across 18 regions-of-interest (ROIs). To assess [18F]flortaucipir specificity and level of detection for tau pathology, correlations between [18F]flortaucipir SUVR and neuritic plaque score and TDP-43 stage were also computed and retention was further assessed in individuals with possible primary age-related tauopathy (PART), defined as Thal phase ≤ 2 and Braak stage I–IV. We found modest-to-strong correlations between in vivo [18F]flortaucipir SUVR and post-mortem tau pathology density in corresponding brain regions in all neocortical regions analyzed (rho-range = 0.61–0.79, p < 0.0001 for all). The detection threshold of [18F]flortaucipir PET was determined to be 0.85% of surface area affected by tau pathology in a temporal meta-ROI, and 0.15% in a larger cortical meta-ROI. No significant associations were found between [18F]flortaucipir SUVRs and post-mortem tau pathology in individuals with possible PART. Further, there was no correlation observed between [18F]flortaucipir and level of amyloid-β neuritic plaque load (rho-range =  – 0.16–0.12; p = 0.48–0.61) or TDP-43 stage (rho-range =  – 0.10 to  – 0.30; p = 0.18–0.65). In conclusion, our in vivo vs post-mortem study shows that the in vivo [18F]flortaucipir PET signal primarily reflects tau pathology, also at relatively low densities of tau proteinopathy, and does not bind substantially to tau neurites in neuritic plaques or in individuals with PART.

[18F]Flortaucipir是一种经FDA批准的tau-PET示踪剂,越来越多地被用于阿尔茨海默病的临床诊断。然而,目前还缺乏将体内 PET 摄取与死后 tau 病理定量及其他合并病理进行大规模比较的研究。在这里,我们研究了 AVID A16 生命末期研究(n = 63)中相应脑区的体内 [18F]flortaucipir PET 摄取与死后 tau 病理定量之间的相关性。所有参与者在死前都接受了[18F]氟替瑞匹PET扫描,随后使用AT8(tau)免疫组化技术进行了详细的死后神经病理学检查。评估了18个感兴趣区(ROI)的[18F]氟替瑞匹标准化摄取值比(SUVRs)与AT8免疫组化之间的相关性。为了评估[18F]flortaucipir对tau病理学的特异性和检测水平,我们还计算了[18F]flortaucipir SUVR与神经斑块评分和TDP-43分期之间的相关性,并进一步评估了可能患有原发性年龄相关tau病(PART)(Thal分期≤2和Braak分期I-IV)的个体的保留率。我们发现,在分析的所有新皮质区域中,体内[18F]氟陶西哌 SUVR 与相应脑区的死后 tau 病理学密度之间存在中度到高度的相关性(rho-range = 0.61-0.79, p < 0.0001)。在颞叶元ROI中,[18F]flortaucipir PET的检测阈值被确定为受tau病理学影响的表面积的0.85%,而在更大的皮层元ROI中,[18F]flortaucipir PET的检测阈值为0.15%。在可能患有PART的患者中,[18F]flortaucipir SUVR与死后tau病理学之间没有发现明显的关联。此外,在[18F]flortaucipir和淀粉样β神经斑块负荷水平(rho-范围=-0.16-0.12;p=0.48-0.61)或TDP-43阶段(rho-范围=-0.10至-0.30;p=0.18-0.65)之间也没有观察到相关性。总之,我们的活体与尸检研究表明,活体[18F]氟陶西哌 PET 信号主要反映 tau 病理学,在 tau 蛋白病变的密度相对较低时也是如此,并且不会与神经里质斑块中的 tau 神经元或 PART 患者的 tau 神经元发生实质性结合。
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引用次数: 0
Dysregulated FOXO1 activity drives skeletal muscle intrinsic dysfunction in amyotrophic lateral sclerosis FOXO1 活性失调导致肌萎缩侧索硬化症患者骨骼肌内在功能障碍
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-16 DOI: 10.1007/s00401-024-02794-y
Mónica Zufiría, Oihane Pikatza-Menoio, Maddi Garciandia-Arcelus, Xabier Bengoetxea, Andrés Jiménez, Amaia Elicegui, María Levchuk, Olatz Arnold-García, Jon Ondaro, Pablo Iruzubieta, Laura Rodríguez-Gómez, Uxoa Fernández-Pelayo, Mikel Muñoz-Oreja, Ana Aiastui, José Manuel García-Verdugo, Vicente Herranz-Pérez, Miren Zulaica, Juan José Poza, Rebeca Ruiz-Onandi, Roberto Fernández-Torrón, Juan Bautista Espinal, Mario Bonilla, Ana Lersundi, Gorka Fernández-Eulate, Javier Riancho, Ainara Vallejo-Illarramendi, Ian James Holt, Amets Sáenz, Edoardo Malfatti, Stéphanie Duguez, Lorea Blázquez, Adolfo López de Munain, Gorka Gerenu, Francisco Gil-Bea, Sonia Alonso-Martín

Amyotrophic Lateral Sclerosis (ALS) is a multisystemic neurodegenerative disorder, with accumulating evidence indicating metabolic disruptions in the skeletal muscle preceding disease symptoms, rather than them manifesting as a secondary consequence of motor neuron (MN) degeneration. Hence, energy homeostasis is deeply implicated in the complex physiopathology of ALS and skeletal muscle has emerged as a key therapeutic target. Here, we describe intrinsic abnormalities in ALS skeletal muscle, both in patient-derived muscle cells and in muscle cell lines with genetic knockdown of genes related to familial ALS, such as TARDBP (TDP-43) and FUS. We found a functional impairment of myogenesis that parallels defects of glucose oxidation in ALS muscle cells. We identified FOXO1 transcription factor as a key mediator of these metabolic and functional features in ALS muscle, via gene expression profiling and biochemical surveys in TDP-43 and FUS-silenced muscle progenitors. Strikingly, inhibition of FOXO1 mitigated the impaired myogenesis in both the genetically modified and the primary ALS myoblasts. In addition, specific in vivo conditional knockdown of TDP-43 or FUS orthologs (TBPH or caz) in Drosophila muscle precursor cells resulted in decreased innervation and profound dysfunction of motor nerve terminals and neuromuscular synapses, accompanied by motor abnormalities and reduced lifespan. Remarkably, these phenotypes were partially corrected by foxo inhibition, bolstering the potential pharmacological management of muscle intrinsic abnormalities associated with ALS. The findings demonstrate an intrinsic muscle dysfunction in ALS, which can be modulated by targeting FOXO factors, paving the way for novel therapeutic approaches that focus on the skeletal muscle as complementary target tissue.

肌萎缩侧索硬化症(ALS)是一种多系统神经退行性疾病,越来越多的证据表明,骨骼肌的代谢紊乱先于疾病症状出现,而不是运动神经元(MN)变性的继发后果。因此,能量平衡与渐冻症复杂的生理病理有密切关系,而骨骼肌已成为关键的治疗靶点。在这里,我们描述了 ALS 骨骼肌的内在异常,既包括源自患者的肌肉细胞,也包括基因敲除与家族性 ALS 相关基因(如 TARDBP (TDP-43) 和 FUS)的肌肉细胞系。我们发现在 ALS 肌肉细胞中存在与葡萄糖氧化缺陷相似的肌生成功能障碍。通过对 TDP-43 和 FUS 沉默的肌肉祖细胞进行基因表达谱分析和生化调查,我们发现 FOXO1 转录因子是 ALS 肌肉中这些代谢和功能特征的关键介导因子。令人震惊的是,抑制 FOXO1 可减轻转基因和原发性 ALS 肌母细胞受损的肌生成。此外,在果蝇肌肉前体细胞中特异性地在体内条件性敲除TDP-43或FUS同源物(TBPH或caz)会导致运动神经末梢和神经肌肉突触的神经支配减少和功能严重失调,并伴有运动异常和寿命缩短。值得注意的是,这些表型可通过抑制 foxo 得到部分纠正,从而增强了对与渐冻症相关的肌肉内在异常进行药物治疗的潜力。这些发现证明了渐冻症的内在肌肉功能障碍可以通过靶向 FOXO 因子来调节,从而为以骨骼肌为补充靶组织的新型治疗方法铺平了道路。
{"title":"Dysregulated FOXO1 activity drives skeletal muscle intrinsic dysfunction in amyotrophic lateral sclerosis","authors":"Mónica Zufiría,&nbsp;Oihane Pikatza-Menoio,&nbsp;Maddi Garciandia-Arcelus,&nbsp;Xabier Bengoetxea,&nbsp;Andrés Jiménez,&nbsp;Amaia Elicegui,&nbsp;María Levchuk,&nbsp;Olatz Arnold-García,&nbsp;Jon Ondaro,&nbsp;Pablo Iruzubieta,&nbsp;Laura Rodríguez-Gómez,&nbsp;Uxoa Fernández-Pelayo,&nbsp;Mikel Muñoz-Oreja,&nbsp;Ana Aiastui,&nbsp;José Manuel García-Verdugo,&nbsp;Vicente Herranz-Pérez,&nbsp;Miren Zulaica,&nbsp;Juan José Poza,&nbsp;Rebeca Ruiz-Onandi,&nbsp;Roberto Fernández-Torrón,&nbsp;Juan Bautista Espinal,&nbsp;Mario Bonilla,&nbsp;Ana Lersundi,&nbsp;Gorka Fernández-Eulate,&nbsp;Javier Riancho,&nbsp;Ainara Vallejo-Illarramendi,&nbsp;Ian James Holt,&nbsp;Amets Sáenz,&nbsp;Edoardo Malfatti,&nbsp;Stéphanie Duguez,&nbsp;Lorea Blázquez,&nbsp;Adolfo López de Munain,&nbsp;Gorka Gerenu,&nbsp;Francisco Gil-Bea,&nbsp;Sonia Alonso-Martín","doi":"10.1007/s00401-024-02794-y","DOIUrl":"10.1007/s00401-024-02794-y","url":null,"abstract":"<div><p>Amyotrophic Lateral Sclerosis (ALS) is a multisystemic neurodegenerative disorder, with accumulating evidence indicating metabolic disruptions in the skeletal muscle preceding disease symptoms, rather than them manifesting as a secondary consequence of motor neuron (MN) degeneration. Hence, energy homeostasis is deeply implicated in the complex physiopathology of ALS and skeletal muscle has emerged as a key therapeutic target. Here, we describe intrinsic abnormalities in ALS skeletal muscle, both in patient-derived muscle cells and in muscle cell lines with genetic knockdown of genes related to familial ALS, such as <i>TARDBP</i> (TDP-43) and <i>FUS</i>. We found a functional impairment of myogenesis that parallels defects of glucose oxidation in ALS muscle cells. We identified FOXO1 transcription factor as a key mediator of these metabolic and functional features in ALS muscle, via gene expression profiling and biochemical surveys in TDP-43 and FUS-silenced muscle progenitors. Strikingly, inhibition of FOXO1 mitigated the impaired myogenesis in both the genetically modified and the primary ALS myoblasts. In addition, specific in vivo conditional knockdown of TDP-43 or FUS orthologs (<i>TBPH</i> or <i>caz</i>) in <i>Drosophila</i> muscle precursor cells resulted in decreased innervation and profound dysfunction of motor nerve terminals and neuromuscular synapses, accompanied by motor abnormalities and reduced lifespan. Remarkably, these phenotypes were partially corrected by <i>foxo</i> inhibition, bolstering the potential pharmacological management of muscle intrinsic abnormalities associated with ALS. The findings demonstrate an intrinsic muscle dysfunction in ALS, which can be modulated by targeting FOXO factors, paving the way for novel therapeutic approaches that focus on the skeletal muscle as complementary target tissue.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02794-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
HOXD12 defines an age-related aggressive subtype of oligodendroglioma HOXD12定义了一种与年龄相关的侵袭性少突胶质细胞瘤亚型
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-11 DOI: 10.1007/s00401-024-02802-1
Nicholas Nuechterlein, Sadie Cimino, Allison Shelbourn, Vinny Ha, Sonali Arora, Sharika Rajan, Linda G. Shapiro, Eric C. Holland, Kenneth Aldape, Tresa McGranahan, Mark R. Gilbert, Patrick J. Cimino

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted has highly variable outcomes that are strongly influenced by patient age. The distribution of oligodendroglioma age is non-Gaussian and reportedly bimodal, which motivated our investigation of age-associated molecular alterations that may drive poorer outcomes. We found that elevated HOXD12 expression was associated with both older patient age and shorter survival in the TCGA (FDR < 0.01, FDR = 1e−5) and the CGGA (p = 0.03, p < 1e−3). HOXD12 gene body hypermethylation was associated with older age, higher WHO grade, and shorter survival in the TCGA (p < 1e−6, p < 0.001, p < 1e−3) and with older age and higher WHO grade in Capper et al. (p < 0.002, p = 0.014). In the TCGA, HOXD12 gene body hypermethylation and elevated expression were independently prognostic of NOTCH1 and PIK3CA mutations, loss of 15q, MYC activation, and standard histopathological features. Single-nucleus RNA and ATAC sequencing data showed that HOXD12 activity was elevated in neoplastic tissue, particularly within cycling and OPC-like cells, and was associated with a stem-like phenotype. A pan-HOX DNA methylation analysis revealed an age and survival-associated HOX-high signature that was tightly associated with HOXD12 gene body methylation. Overall, HOXD12 expression and gene body hypermethylation were associated with an older, atypically aggressive subtype of oligodendroglioma.

IDH突变和1p/19q编码缺失的少突胶质细胞瘤的预后变化很大,受患者年龄的影响很大。少突胶质细胞瘤的年龄分布是非高斯分布,据报道是双峰分布,这促使我们研究可能导致较差预后的年龄相关分子改变。我们发现,在 TCGA(FDR <0.01,FDR = 1e-5)和 CGGA(p = 0.03,p <1e-3)中,HOXD12 表达升高与患者年龄增大和生存期缩短有关。在TCGA(p <1e-6,p <0.001,p <1e-3)和Capper等(p <0.002,p = 0.014)中,HOXD12基因体超甲基化与年龄较大、WHO分级较高和生存期较短有关。在TCGA中,HOXD12基因体超甲基化和表达升高与NOTCH1和PIK3CA突变、15q缺失、MYC活化和标准组织病理学特征无关。单核 RNA 和 ATAC 测序数据显示,HOXD12 活性在肿瘤组织中升高,尤其是在循环细胞和 OPC 样细胞中,并且与干样表型相关。泛HOX DNA甲基化分析显示,与年龄和存活率相关的HOX-高特征与HOXD12基因体甲基化密切相关。总体而言,HOXD12的表达和基因体的高甲基化与年龄较大、侵袭性不典型的少突胶质细胞瘤亚型有关。
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引用次数: 0
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
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Acta Neuropathologica
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