APOEε4 is the major genetic risk factor for sporadic Alzheimer's disease (AD). Although APOEε4 is known to promote Aβ pathology, recent data also support an effect of APOE polymorphism on phosphorylated Tau (pTau) pathology. To elucidate these potential effects, the pTau interactome was analyzed across APOE genotypes in the frontal cortex of 10 advanced AD cases (n = 5 APOEε3/ε3 and n = 5 APOEε4/ε4), using a combination of anti-pTau pS396/pS404 (PHF1) immunoprecipitation (IP) and mass spectrometry (MS). This proteomic approach was complemented by an analysis of anti-pTau PHF1 and anti-Aβ 4G8 immunohistochemistry, performed in the frontal cortex of 21 advanced AD cases (n = 11 APOEε3/ε3 and n = 10 APOEε4/ε4). Our dataset includes 1130 and 1330 proteins enriched in IPPHF1 samples from APOEε3/ε3 and APOEε4/ε4 groups (fold change ≥ 1.50, IPPHF1 vs IPIgG ctrl). We identified 80 and 68 proteins as probable pTau interactors in APOEε3/ε3 and APOEε4/ε4 groups, respectively (SAINT score ≥ 0.80; false discovery rate (FDR) ≤ 5%). A total of 47/80 proteins were identified as more likely to interact with pTau in APOEε3/ε3 vs APOEε4/ε4 cases. Functional enrichment analyses showed that they were significantly associated with the nucleoplasm compartment and involved in RNA processing. In contrast, 35/68 proteins were identified as more likely to interact with pTau in APOEε4/ε4 vs APOEε3/ε3 cases. They were significantly associated with the synaptic compartment and involved in cellular transport. A characterization of Tau pathology in the frontal cortex showed a higher density of plaque-associated neuritic crowns, made of dystrophic axons and synapses, in APOEε4 carriers. Cerebral amyloid angiopathy was more frequent and severe in APOEε4/ε4 cases. Our study supports an influence of APOE genotype on pTau-subcellular location in AD. These results suggest a facilitation of pTau progression to Aβ-affected brain regions in APOEε4 carriers, paving the way to the identification of new therapeutic targets.
{"title":"The influence of APOE<sup>ε4</sup> on the pTau interactome in sporadic Alzheimer's disease.","authors":"Manon Thierry, Jackeline Ponce, Mitchell Martà-Ariza, Manor Askenazi, Arline Faustin, Dominique Leitner, Geoffrey Pires, Evgeny Kanshin, Eleanor Drummond, Beatrix Ueberheide, Thomas Wisniewski","doi":"10.1007/s00401-024-02744-8","DOIUrl":"10.1007/s00401-024-02744-8","url":null,"abstract":"<p><p>APOE<sup>ε4</sup> is the major genetic risk factor for sporadic Alzheimer's disease (AD). Although APOE<sup>ε4</sup> is known to promote Aβ pathology, recent data also support an effect of APOE polymorphism on phosphorylated Tau (pTau) pathology. To elucidate these potential effects, the pTau interactome was analyzed across APOE genotypes in the frontal cortex of 10 advanced AD cases (n = 5 APOE<sup>ε3/ε3</sup> and n = 5 APOE<sup>ε4/ε4</sup>), using a combination of anti-pTau pS396/pS404 (PHF1) immunoprecipitation (IP) and mass spectrometry (MS). This proteomic approach was complemented by an analysis of anti-pTau PHF1 and anti-Aβ 4G8 immunohistochemistry, performed in the frontal cortex of 21 advanced AD cases (n = 11 APOE<sup>ε3/ε3</sup> and n = 10 APOE<sup>ε4/ε4</sup>). Our dataset includes 1130 and 1330 proteins enriched in IP<sub>PHF1</sub> samples from APOE<sup>ε3/ε3</sup> and APOE<sup>ε4/ε4</sup> groups (fold change ≥ 1.50, IP<sub>PHF1</sub> vs IP<sub>IgG ctrl</sub>). We identified 80 and 68 proteins as probable pTau interactors in APOE<sup>ε3/ε3</sup> and APOE<sup>ε4/ε4</sup> groups, respectively (SAINT score ≥ 0.80; false discovery rate (FDR) ≤ 5%). A total of 47/80 proteins were identified as more likely to interact with pTau in APOE<sup>ε3/ε3</sup> vs APOE<sup>ε4/ε4</sup> cases. Functional enrichment analyses showed that they were significantly associated with the nucleoplasm compartment and involved in RNA processing. In contrast, 35/68 proteins were identified as more likely to interact with pTau in APOE<sup>ε4/ε4</sup> vs APOE<sup>ε3/ε3</sup> cases. They were significantly associated with the synaptic compartment and involved in cellular transport. A characterization of Tau pathology in the frontal cortex showed a higher density of plaque-associated neuritic crowns, made of dystrophic axons and synapses, in APOE<sup>ε4</sup> carriers. Cerebral amyloid angiopathy was more frequent and severe in APOE<sup>ε4/ε4</sup> cases. Our study supports an influence of APOE genotype on pTau-subcellular location in AD. These results suggest a facilitation of pTau progression to Aβ-affected brain regions in APOE<sup>ε4</sup> carriers, paving the way to the identification of new therapeutic targets.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11108952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141074591","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}
Pub Date : 2024-05-21DOI: 10.1007/s00401-024-02742-w
Alyse de Boer, Aletta M R van den Bosch, Nienke J Mekkes, Nina L Fransen, Ekaterina Dagkesamanskaia, Eric Hoekstra, Jörg Hamann, Joost Smolders, Inge Huitinga, Inge R Holtman
Multiple sclerosis (MS) is a heterogeneous neurological disorder with regards to clinical presentation and pathophysiology. Here, we investigated the heterogeneity of MS by performing an exploratory factor analysis on quantitative and qualitative neuropathology data collected for 226 MS donors in the Netherlands Brain Bank autopsy cohort. Three promising dimensions were identified and subsequently validated with clinical, neuropathological, and genetic data. Dimension 1 ranged from a predominance of remyelinated and inactive lesions to extensive pathological changes, higher proportions of active and mixed lesions, and foamy microglia morphology. This pattern was positively correlated with more severe disease, the presence of B and T cells, and neuroaxonal damage. Scoring high on dimension 2 was associated with active lesions, reactive sites, and the presence of nodules. These donors had less severe disease, a specific pattern of cortical lesions, and MS risk variants in the human leukocyte antigen region, the latter indicating a connection between disease onset and this neuropathological dimension. Donors scoring high on dimension 3 showed increased lesional pathology with relatively more mixed and inactive lesions and ramified microglia morphology. This pattern was associated with longer disease duration, subpial cortical lesions, less involvement of the adaptive immune system, and less axonal damage. Taken together, the three dimensions may represent (1) demyelination and immune cell activity associated with pathological and clinical progression, (2) microglia (re)activity and possibly lesion initiation, and (3) loss of lesion activity and scar formation. Our findings highlight that a thorough understanding of the interplay between multiple pathological characteristics is crucial to understand the heterogeneity of MS pathology, as well as its association with genetic predictors and disease outcomes. The scores of donors on the dimensions can serve as an important starting point for further disentanglement of MS heterogeneity and translation into observations and interventions in living cohorts with MS.
多发性硬化症(MS)在临床表现和病理生理学方面是一种异质性神经系统疾病。在此,我们通过对荷兰脑库尸检队列中 226 名多发性硬化症供体的定量和定性神经病理学数据进行探索性因子分析,研究了多发性硬化症的异质性。结果发现了三个有前景的维度,并随后通过临床、神经病理学和遗传学数据进行了验证。维度 1 的范围从再髓鞘化和非活动性病变为主到广泛的病理变化、较高比例的活动性和混合性病变以及泡沫状小胶质细胞形态。这种模式与更严重的疾病、B 细胞和 T 细胞的存在以及神经轴损伤呈正相关。维度 2 的高分与活动性病变、反应性部位和结节的存在有关。这些捐献者的病情较轻,皮质病变模式特殊,人类白细胞抗原区域存在多发性硬化症风险变异,后者表明发病与这一神经病理学维度有关。在维度3上得分较高的供体表现出更多的病变病理,混合性和非活动性病变相对较多,小胶质细胞形态呈横纹状。这种模式与较长的病程、皮质下病变、较少的适应性免疫系统参与和较少的轴突损伤有关。综合来看,这三个维度可能代表(1)与病理和临床进展相关的脱髓鞘和免疫细胞活动,(2)小胶质细胞(再)活动和可能的病变启动,以及(3)病变活动消失和瘢痕形成。我们的研究结果突出表明,透彻了解多种病理特征之间的相互作用对于了解多发性硬化症病理的异质性及其与遗传预测因素和疾病预后的关联至关重要。捐献者在这些维度上的得分可以作为一个重要的起点,进一步揭示多发性硬化症的异质性,并将其转化为对多发性硬化症患者群体的观察和干预。
{"title":"Disentangling the heterogeneity of multiple sclerosis through identification of independent neuropathological dimensions.","authors":"Alyse de Boer, Aletta M R van den Bosch, Nienke J Mekkes, Nina L Fransen, Ekaterina Dagkesamanskaia, Eric Hoekstra, Jörg Hamann, Joost Smolders, Inge Huitinga, Inge R Holtman","doi":"10.1007/s00401-024-02742-w","DOIUrl":"10.1007/s00401-024-02742-w","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is a heterogeneous neurological disorder with regards to clinical presentation and pathophysiology. Here, we investigated the heterogeneity of MS by performing an exploratory factor analysis on quantitative and qualitative neuropathology data collected for 226 MS donors in the Netherlands Brain Bank autopsy cohort. Three promising dimensions were identified and subsequently validated with clinical, neuropathological, and genetic data. Dimension 1 ranged from a predominance of remyelinated and inactive lesions to extensive pathological changes, higher proportions of active and mixed lesions, and foamy microglia morphology. This pattern was positively correlated with more severe disease, the presence of B and T cells, and neuroaxonal damage. Scoring high on dimension 2 was associated with active lesions, reactive sites, and the presence of nodules. These donors had less severe disease, a specific pattern of cortical lesions, and MS risk variants in the human leukocyte antigen region, the latter indicating a connection between disease onset and this neuropathological dimension. Donors scoring high on dimension 3 showed increased lesional pathology with relatively more mixed and inactive lesions and ramified microglia morphology. This pattern was associated with longer disease duration, subpial cortical lesions, less involvement of the adaptive immune system, and less axonal damage. Taken together, the three dimensions may represent (1) demyelination and immune cell activity associated with pathological and clinical progression, (2) microglia (re)activity and possibly lesion initiation, and (3) loss of lesion activity and scar formation. Our findings highlight that a thorough understanding of the interplay between multiple pathological characteristics is crucial to understand the heterogeneity of MS pathology, as well as its association with genetic predictors and disease outcomes. The scores of donors on the dimensions can serve as an important starting point for further disentanglement of MS heterogeneity and translation into observations and interventions in living cohorts with MS.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11108935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070255","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}
Pub Date : 2024-05-18DOI: 10.1007/s00401-024-02729-7
Michael J. Ellis, Christiana Lekka, Katie L. Holden, Hanna Tulmin, Faheem Seedat, Darragh P. O’Brien, Shalinee Dhayal, Marie-Louise Zeissler, Jakob G. Knudsen, Benedikt M. Kessler, Noel G. Morgan, John A. Todd, Sarah J. Richardson, M. Irina Stefana
Antibodies are essential research tools whose performance directly impacts research conclusions and reproducibility. Owing to its central role in Alzheimer’s disease and other dementias, hundreds of distinct antibody clones have been developed against the microtubule-associated protein Tau and its multiple proteoforms. Despite this breadth of offer, limited understanding of their performance and poor antibody selectivity have hindered research progress. Here, we validate a large panel of Tau antibodies by Western blot (79 reagents) and immunohistochemistry (35 reagents). We address the reagents’ ability to detect the target proteoform, selectivity, the impact of protein phosphorylation on antibody binding and performance in human brain samples. While most antibodies detected Tau at high levels, many failed to detect it at lower, endogenous levels. By WB, non-selective binding to other proteins affected over half of the antibodies tested, with several cross-reacting with the related MAP2 protein, whereas the “oligomeric Tau” T22 antibody reacted with monomeric Tau by WB, thus calling into question its specificity to Tau oligomers. Despite the presumption that “total” Tau antibodies are agnostic to post-translational modifications, we found that phosphorylation partially inhibits binding for many such antibodies, including the popular Tau-5 clone. We further combine high-sensitivity reagents, mass-spectrometry proteomics and cDNA sequencing to demonstrate that presumptive Tau “knockout” human cells continue to express residual protein arising through exon skipping, providing evidence of previously unappreciated gene plasticity. Finally, probing of human brain samples with a large panel of antibodies revealed the presence of C-term-truncated versions of all main Tau brain isoforms in both control and tauopathy donors. Ultimately, we identify a validated panel of Tau antibodies that can be employed in Western blotting and/or immunohistochemistry to reliably detect even low levels of Tau expression with high selectivity. This work represents an extensive resource that will enable the re-interpretation of published data, improve reproducibility in Tau research, and overall accelerate scientific progress.
抗体是重要的研究工具,其性能直接影响研究结论和可重复性。由于 Tau 在阿尔茨海默病和其他痴呆症中的核心作用,针对微管相关蛋白 Tau 及其多种蛋白形式开发了数百种不同的抗体克隆。尽管提供的抗体种类繁多,但对其性能的了解有限以及抗体选择性差阻碍了研究的进展。在此,我们通过 Western 印迹(79 种试剂)和免疫组化(35 种试剂)验证了大量 Tau 抗体。我们讨论了这些试剂检测目标蛋白形式的能力、选择性、蛋白磷酸化对抗体结合的影响以及在人脑样本中的表现。虽然大多数抗体都能检测到高水平的 Tau,但许多抗体却不能检测到较低水平的内源性 Tau。通过WB检测,与其他蛋白质的非选择性结合影响了半数以上的受试抗体,其中几种抗体与相关的MAP2蛋白发生交叉反应,而 "寡聚Tau "T22抗体则与单体Tau发生WB反应,从而使其对Tau寡聚体的特异性受到质疑。尽管 "全 "Tau抗体与翻译后修饰无关,但我们发现磷酸化会部分抑制许多此类抗体的结合,包括流行的Tau-5克隆。我们进一步将高灵敏度试剂、质谱蛋白质组学和 cDNA 测序结合起来,证明推定的 Tau "敲除 "人体细胞继续表达通过外显子跳越产生的残余蛋白,为以前未被认识到的基因可塑性提供了证据。最后,用大量抗体对人脑样本进行检测发现,在对照组和牛磺酸脑病供体中都存在所有主要Tau脑异构体的C端截短版本。最终,我们确定了一组经过验证的 Tau 抗体,可用于 Western 印迹分析和/或免疫组化,以高选择性可靠地检测低水平的 Tau 表达。这项工作代表了一种广泛的资源,将有助于重新解释已发表的数据,提高 Tau 研究的可重复性,并全面加速科学进步。
{"title":"Identification of high-performing antibodies for the reliable detection of Tau proteoforms by Western blotting and immunohistochemistry","authors":"Michael J. Ellis, Christiana Lekka, Katie L. Holden, Hanna Tulmin, Faheem Seedat, Darragh P. O’Brien, Shalinee Dhayal, Marie-Louise Zeissler, Jakob G. Knudsen, Benedikt M. Kessler, Noel G. Morgan, John A. Todd, Sarah J. Richardson, M. Irina Stefana","doi":"10.1007/s00401-024-02729-7","DOIUrl":"https://doi.org/10.1007/s00401-024-02729-7","url":null,"abstract":"<p>Antibodies are essential research tools whose performance directly impacts research conclusions and reproducibility. Owing to its central role in Alzheimer’s disease and other dementias, hundreds of distinct antibody clones have been developed against the microtubule-associated protein Tau and its multiple proteoforms. Despite this breadth of offer, limited understanding of their performance and poor antibody selectivity have hindered research progress. Here, we validate a large panel of Tau antibodies by Western blot (79 reagents) and immunohistochemistry (35 reagents). We address the reagents’ ability to detect the target proteoform, selectivity, the impact of protein phosphorylation on antibody binding and performance in human brain samples. While most antibodies detected Tau at high levels, many failed to detect it at lower, endogenous levels. By WB, non-selective binding to other proteins affected over half of the antibodies tested, with several cross-reacting with the related MAP2 protein, whereas the “oligomeric Tau” T22 antibody reacted with monomeric Tau by WB, thus calling into question its specificity to Tau oligomers. Despite the presumption that “total” Tau antibodies are agnostic to post-translational modifications, we found that phosphorylation partially inhibits binding for many such antibodies, including the popular Tau-5 clone. We further combine high-sensitivity reagents, mass-spectrometry proteomics and cDNA sequencing to demonstrate that presumptive Tau “knockout” human cells continue to express residual protein arising through exon skipping, providing evidence of previously unappreciated gene plasticity. Finally, probing of human brain samples with a large panel of antibodies revealed the presence of C-term-truncated versions of all main Tau brain isoforms in both control and tauopathy donors. Ultimately, we identify a validated panel of Tau antibodies that can be employed in Western blotting and/or immunohistochemistry to reliably detect even low levels of Tau expression with high selectivity. This work represents an extensive resource that will enable the re-interpretation of published data, improve reproducibility in Tau research, and overall accelerate scientific progress.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140953964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-18DOI: 10.1007/s00401-024-02739-5
Nourhan Shebl, Mohamed Salama
{"title":"From metabolomics to proteomics: understanding the role of dopa decarboxylase in Parkinson’s disease. Scientific commentary on: “Comprehensive proteomics of CSF, plasma, and urine identify DDC and other biomarkers of early Parkinson’s disease”","authors":"Nourhan Shebl, Mohamed Salama","doi":"10.1007/s00401-024-02739-5","DOIUrl":"https://doi.org/10.1007/s00401-024-02739-5","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140954255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-17DOI: 10.1007/s00401-024-02741-x
Chao Qi, Ryota Kobayashi, Shinobu Kawakatsu, Fuyuki Kametani, Sjors H. W. Scheres, Michel Goedert, Masato Hasegawa
Dominantly inherited mutation D395G in the gene encoding valosin-containing protein causes vacuolar tauopathy, a type of behavioural-variant frontotemporal dementia, with marked vacuolation and abundant filamentous tau inclusions made of all six brain isoforms. Here we report that tau inclusions were concentrated in layers II/III of the frontotemporal cortex in a case of vacuolar tauopathy. By electron cryomicroscopy, tau filaments had the chronic traumatic encephalopathy (CTE) fold. Tau inclusions of vacuolar tauopathy share this cortical location and the tau fold with CTE, subacute sclerosing panencephalitis and amyotrophic lateral sclerosis/parkinsonism-dementia complex, which are believed to be environmentally induced. Vacuolar tauopathy is the first inherited disease with the CTE tau fold.
编码含缬氨酸蛋白的基因中的显性遗传突变 D395G 会导致空泡性 tau 病,这是一种行为变异型额颞叶痴呆症,具有明显的空泡化和丰富的丝状 tau 包涵体,由所有六种脑异构体组成。在这里,我们报告了一个空泡型tau病病例,其tau包涵体集中在额颞叶皮层的II/III层。通过电子冷冻显微镜观察,tau丝具有慢性创伤性脑病(CTE)的特征。空泡型tau蛋白病的tau包涵体与CTE、亚急性硬化性泛脑炎和肌萎缩性脊髓侧索硬化症/帕金森氏症-痴呆综合症具有相同的皮质位置和tau褶皱,这些疾病被认为是由环境诱发的。空泡型tau蛋白病是第一种具有CTE tau蛋白褶皱的遗传性疾病。
{"title":"Tau filaments with the chronic traumatic encephalopathy fold in a case of vacuolar tauopathy with VCP mutation D395G","authors":"Chao Qi, Ryota Kobayashi, Shinobu Kawakatsu, Fuyuki Kametani, Sjors H. W. Scheres, Michel Goedert, Masato Hasegawa","doi":"10.1007/s00401-024-02741-x","DOIUrl":"https://doi.org/10.1007/s00401-024-02741-x","url":null,"abstract":"<p>Dominantly inherited mutation D395G in the gene encoding valosin-containing protein causes vacuolar tauopathy, a type of behavioural-variant frontotemporal dementia, with marked vacuolation and abundant filamentous tau inclusions made of all six brain isoforms. Here we report that tau inclusions were concentrated in layers II/III of the frontotemporal cortex in a case of vacuolar tauopathy. By electron cryomicroscopy, tau filaments had the chronic traumatic encephalopathy (CTE) fold. Tau inclusions of vacuolar tauopathy share this cortical location and the tau fold with CTE, subacute sclerosing panencephalitis and amyotrophic lateral sclerosis/parkinsonism-dementia complex, which are believed to be environmentally induced. Vacuolar tauopathy is the first inherited disease with the CTE tau fold.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140953428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-17DOI: 10.1007/s00401-024-02736-8
Andrew L. Lin, Vasilisa A. Rudneva, Allison L. Richards, Yanming Zhang, Hyung Jun Woo, Marc Cohen, Jamie Tisnado, Nazanin Majd, Sharon L. Wardlaw, Gabrielle Page-Wilson, Soma Sengupta, Frances Chow, Bernard Goichot, Byram H. Ozer, Jorg Dietrich, Lisa Nachtigall, Arati Desai, Tina Alano, Shahiba Ogilive, David B. Solit, Tejus A. Bale, Marc Rosenblum, Mark T. A. Donoghue, Eliza B. Geer, Viviane Tabar
Pituitary neuroendocrine tumors (PitNETs) exhibiting aggressive, treatment-refractory behavior are the rare subset that progress after surgery, conventional medical therapies, and an initial course of radiation and are characterized by unrelenting growth and/or metastatic dissemination. Two groups of patients with PitNETs were sequenced: a prospective group of patients (n = 66) who consented to sequencing prior to surgery and a retrospective group (n = 26) comprised of aggressive/higher risk PitNETs. A higher mutational burden and fraction of loss of heterozygosity (LOH) was found in the aggressive, treatment-refractory PitNETs compared to the benign tumors (p = 1.3 × 10−10 and p = 8.5 × 10−9, respectively). Within the corticotroph lineage, a characteristic pattern of recurrent chromosomal LOH in 12 specific chromosomes was associated with treatment-refractoriness (occurring in 11 of 14 treatment-refractory versus 1 of 14 benign corticotroph PitNETs, p = 1.7 × 10−4). Across the cohort, a higher fraction of LOH was identified in tumors with TP53 mutations (p = 3.3 × 10−8). A machine learning approach identified loss of heterozygosity as the most predictive variable for aggressive, treatment-refractory behavior, outperforming the most common gene-level alteration, TP53, with an accuracy of 0.88 (95% CI: 0.70–0.96). Aggressive, treatment-refractory PitNETs are characterized by significant aneuploidy due to widespread chromosomal LOH, most prominently in the corticotroph tumors. This LOH predicts treatment-refractoriness with high accuracy and represents a novel biomarker for this poorly defined PitNET category.
{"title":"Genome-wide loss of heterozygosity predicts aggressive, treatment-refractory behavior in pituitary neuroendocrine tumors","authors":"Andrew L. Lin, Vasilisa A. Rudneva, Allison L. Richards, Yanming Zhang, Hyung Jun Woo, Marc Cohen, Jamie Tisnado, Nazanin Majd, Sharon L. Wardlaw, Gabrielle Page-Wilson, Soma Sengupta, Frances Chow, Bernard Goichot, Byram H. Ozer, Jorg Dietrich, Lisa Nachtigall, Arati Desai, Tina Alano, Shahiba Ogilive, David B. Solit, Tejus A. Bale, Marc Rosenblum, Mark T. A. Donoghue, Eliza B. Geer, Viviane Tabar","doi":"10.1007/s00401-024-02736-8","DOIUrl":"https://doi.org/10.1007/s00401-024-02736-8","url":null,"abstract":"<p>Pituitary neuroendocrine tumors (PitNETs) exhibiting aggressive, treatment-refractory behavior are the rare subset that progress after surgery, conventional medical therapies, and an initial course of radiation and are characterized by unrelenting growth and/or metastatic dissemination. Two groups of patients with PitNETs were sequenced: a prospective group of patients (<i>n</i> = 66) who consented to sequencing prior to surgery and a retrospective group (<i>n</i> = 26) comprised of aggressive/higher risk PitNETs. A higher mutational burden and fraction of loss of heterozygosity (LOH) was found in the aggressive, treatment-refractory PitNETs compared to the benign tumors (<i>p</i> = 1.3 × 10<sup>−10</sup> and <i>p</i> = 8.5 × 10<sup>−9</sup>, respectively). Within the corticotroph lineage, a characteristic pattern of recurrent chromosomal LOH in 12 specific chromosomes was associated with treatment-refractoriness (occurring in 11 of 14 treatment-refractory versus 1 of 14 benign corticotroph PitNETs, <i>p</i> = 1.7 × 10<sup>−4</sup>). Across the cohort, a higher fraction of LOH was identified in tumors with <i>TP53</i> mutations (<i>p</i> = 3.3 × 10<sup>−8</sup>). A machine learning approach identified loss of heterozygosity as the most predictive variable for aggressive, treatment-refractory behavior, outperforming the most common gene-level alteration, <i>TP53</i>, with an accuracy of 0.88 (95% CI: 0.70–0.96). Aggressive, treatment-refractory PitNETs are characterized by significant aneuploidy due to widespread chromosomal LOH, most prominently in the corticotroph tumors. This LOH predicts treatment-refractoriness with high accuracy and represents a novel biomarker for this poorly defined PitNET category.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140953492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson's disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.
肌萎缩侧索硬化症/帕金森病-痴呆综合症(ALS/PDC)是一种罕见的复杂神经系统疾病,主要发生在西太平洋岛屿,包括日本、关岛和巴布亚地区。由于患者的症状与典型的肌萎缩侧索硬化症(ALS)或帕金森病(PD)相似,这种神秘的疾病一直备受医学界关注。与众不同的是,对患者大脑的尸检显示存在α-突触核蛋白聚集体和TDP-43,这分别是帕金森病和典型渐冻人症的特征。磷酸化 tau 的检测使这些观察结果变得更加复杂,突出了 ALS/PDC 蛋白病理的多面性。这种疾病的病因学基础仍未确定,遗传学研究也尚未给出结论性答案。不过,新出现的证据表明,维持大脑健康的关键细胞星形胶质细胞与神经退行性病变的发病有关,并可能在 ALS/PDC 的发病机制中发挥重要作用。利用先进的诱导多能干细胞技术,我们的团队培养了多个星形胶质细胞系,以进一步研究日本 ALS/PDC(Kii ALS/PDC)变异型。当疾病星形胶质细胞与健康对照组比较时,CHCHD2 成为一个明显失调的基因。我们的分析还揭示了特定通路激活的失衡:与星形胶质细胞纤毛功能障碍相关的通路(已知参与神经退行性变),以及与主要神经系统疾病(包括典型 ALS 和 PD)相关的通路。进一步的深入研究发现,受影响的星形胶质细胞的线粒体形态和代谢过程出现异常。一个特别引人注目的观察结果是,在 Kii ALS/PDC 患者的脊髓、运动皮层和眼球运动核中,CHCHD2 的表达减少。总之,我们的研究结果表明,Kii ALS/PDC星形胶质细胞对神经元的支持可能会减少,这强调了探索CHCHD2在维持线粒体健康方面的作用及其对该疾病的影响的必要性。
{"title":"Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes.","authors":"Nicolas Leventoux, Satoru Morimoto, Mitsuru Ishikawa, Shiho Nakamura, Fumiko Ozawa, Reona Kobayashi, Hirotaka Watanabe, Sopak Supakul, Satoshi Okamoto, Zhi Zhou, Hiroya Kobayashi, Chris Kato, Yoshifumi Hirokawa, Ikuko Aiba, Shinichi Takahashi, Shinsuke Shibata, Masaki Takao, Mari Yoshida, Fumito Endo, Koji Yamanaka, Yasumasa Kokubo, Hideyuki Okano","doi":"10.1007/s00401-024-02734-w","DOIUrl":"10.1007/s00401-024-02734-w","url":null,"abstract":"<p><p>Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson's disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140943547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-12DOI: 10.1007/s00401-024-02740-y
Ulrich Schüller, Antonia Gocke, Shweta Godbole, Claire Delbridge, Christian Thomas, Julia E Neumann
{"title":"Anaplastic histology and distinct molecular features in a small series of spinal cord ependymomas.","authors":"Ulrich Schüller, Antonia Gocke, Shweta Godbole, Claire Delbridge, Christian Thomas, Julia E Neumann","doi":"10.1007/s00401-024-02740-y","DOIUrl":"10.1007/s00401-024-02740-y","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11089008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140908055","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}
Pub Date : 2024-05-09DOI: 10.1007/s00401-024-02733-x
Farina Windener, Laureen Grewing, Christian Thomas, Marie-France Dorion, Marie Otteken, Lara Kular, Maja Jagodic, Jack Antel, Stefanie Albrecht, Tanja Kuhlmann
Aging affects all cell types in the CNS and plays an important role in CNS diseases. However, the underlying molecular mechanisms driving these age-associated changes and their contribution to diseases are only poorly understood. The white matter in the aging brain as well as in diseases, such as Multiple sclerosis is characterized by subtle abnormalities in myelin sheaths and paranodes, suggesting that oligodendrocytes, the myelin-maintaining cells of the CNS, lose the capacity to preserve a proper myelin structure and potentially function in age and certain diseases. Here, we made use of directly converted oligodendrocytes (dchiOL) from young, adult and old human donors to study age-associated changes. dchiOL from all three age groups differentiated in an comparable manner into O4 + immature oligodendrocytes, but the proportion of MBP + mature dchiOL decreased with increasing donor age. This was associated with an increased ROS production and upregulation of cellular senescence markers such as CDKN1A, CDKN2A in old dchiOL. Comparison of the transcriptomic profiles of dchiOL from adult and old donors revealed 1324 differentially regulated genes with limited overlap with transcriptomic profiles of the donors’ fibroblasts or published data sets from directly converted human neurons or primary rodent oligodendroglial lineage cells. Methylome analyses of dchiOL and human white matter tissue samples demonstrate that chronological and epigenetic age correlate in CNS white matter as well as in dchiOL and resulted in the identification of an age-specific epigenetic signature. Furthermore, we observed an accelerated epigenetic aging of the myelinated, normal appearing white matter of multiple sclerosis (MS) patients compared to healthy individuals. Impaired differentiation and upregulation of cellular senescence markers could be induced in young dchiOL in vitro using supernatants from pro-inflammatory microglia. In summary, our data suggest that physiological aging as well as inflammation-induced cellular senescence contribute to oligodendroglial pathology in inflammatory demyelinating diseases such as MS.
{"title":"Physiological aging and inflammation-induced cellular senescence may contribute to oligodendroglial dysfunction in MS","authors":"Farina Windener, Laureen Grewing, Christian Thomas, Marie-France Dorion, Marie Otteken, Lara Kular, Maja Jagodic, Jack Antel, Stefanie Albrecht, Tanja Kuhlmann","doi":"10.1007/s00401-024-02733-x","DOIUrl":"https://doi.org/10.1007/s00401-024-02733-x","url":null,"abstract":"<p>Aging affects all cell types in the CNS and plays an important role in CNS diseases. However, the underlying molecular mechanisms driving these age-associated changes and their contribution to diseases are only poorly understood. The white matter in the aging brain as well as in diseases, such as Multiple sclerosis is characterized by subtle abnormalities in myelin sheaths and paranodes, suggesting that oligodendrocytes, the myelin-maintaining cells of the CNS, lose the capacity to preserve a proper myelin structure and potentially function in age and certain diseases. Here, we made use of directly converted oligodendrocytes (dchiOL) from young, adult and old human donors to study age-associated changes. dchiOL from all three age groups differentiated in an comparable manner into O4 + immature oligodendrocytes, but the proportion of MBP + mature dchiOL decreased with increasing donor age. This was associated with an increased ROS production and upregulation of cellular senescence markers such as <i>CDKN1A, CDKN2A</i> in old dchiOL. Comparison of the transcriptomic profiles of dchiOL from adult and old donors revealed 1324 differentially regulated genes with limited overlap with transcriptomic profiles of the donors’ fibroblasts or published data sets from directly converted human neurons or primary rodent oligodendroglial lineage cells. Methylome analyses of dchiOL and human white matter tissue samples demonstrate that chronological and epigenetic age correlate in CNS white matter as well as in dchiOL and resulted in the identification of an age-specific epigenetic signature. Furthermore, we observed an accelerated epigenetic aging of the myelinated, normal appearing white matter of multiple sclerosis (MS) patients compared to healthy individuals. Impaired differentiation and upregulation of cellular senescence markers could be induced in young dchiOL in vitro using supernatants from pro-inflammatory microglia. In summary, our data suggest that physiological aging as well as inflammation-induced cellular senescence contribute to oligodendroglial pathology in inflammatory demyelinating diseases such as MS.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140895377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}