Pub Date : 2024-10-03DOI: 10.1186/s40478-024-01867-z
Elodie Chevalier, Mickael Audrain, Monisha Ratnam, Romain Ollier, Aline Fuchs, Kasia Piorkowska, Andrea Pfeifer, Marie Kosco-Vilbois, Tamara Seredenina, Tariq Afroz
Abnormal cytoplasmic localization and accumulation of pathological transactive response DNA binding protein of 43 kDa (TDP-43) underlies several devastating diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). A key element is the correlation between disease progression and spatio-temporal propagation of TDP-43-mediated pathology in the central nervous system. Several lines of evidence support the concept of templated aggregation and cell to cell spreading of pathological TDP-43. To further investigate this mechanism in vivo, we explored the efficacy of capturing and masking the seeding-competent region of extracellular TDP-43 species. For this, we generated a novel monoclonal antibody (mAb), ACI-6677, that targets the pathogenic protease-resistant amyloid core of TDP-43. ACI-6677 has a picomolar binding affinity for TDP-43 and is capable of binding to all C-terminal TDP-43 fragments. In vitro, ACI-6677 inhibited TDP-43 aggregation and boosted removal of pathological TDP-43 aggregates by phagocytosis. When injecting FTLD-TDP brain extracts unilaterally in the CamKIIa-hTDP-43NLSm mouse model, ACI-6677 significantly limited the induction of phosphorylated TDP-43 (pTDP-43) inclusions. Strikingly, on the contralateral side, the mAb significantly prevented pTDP-43 inclusion appearance exemplifying blocking of the spreading process. Taken together, these data demonstrate for the first time that an immunotherapy targeting the protease-resistant amyloid core of TDP-43 has the potential to restrict spreading, substantially slowing or stopping progression of disease.
{"title":"Targeting the TDP-43 low complexity domain blocks spreading of pathology in a mouse model of ALS/FTD.","authors":"Elodie Chevalier, Mickael Audrain, Monisha Ratnam, Romain Ollier, Aline Fuchs, Kasia Piorkowska, Andrea Pfeifer, Marie Kosco-Vilbois, Tamara Seredenina, Tariq Afroz","doi":"10.1186/s40478-024-01867-z","DOIUrl":"10.1186/s40478-024-01867-z","url":null,"abstract":"<p><p>Abnormal cytoplasmic localization and accumulation of pathological transactive response DNA binding protein of 43 kDa (TDP-43) underlies several devastating diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). A key element is the correlation between disease progression and spatio-temporal propagation of TDP-43-mediated pathology in the central nervous system. Several lines of evidence support the concept of templated aggregation and cell to cell spreading of pathological TDP-43. To further investigate this mechanism in vivo, we explored the efficacy of capturing and masking the seeding-competent region of extracellular TDP-43 species. For this, we generated a novel monoclonal antibody (mAb), ACI-6677, that targets the pathogenic protease-resistant amyloid core of TDP-43. ACI-6677 has a picomolar binding affinity for TDP-43 and is capable of binding to all C-terminal TDP-43 fragments. In vitro, ACI-6677 inhibited TDP-43 aggregation and boosted removal of pathological TDP-43 aggregates by phagocytosis. When injecting FTLD-TDP brain extracts unilaterally in the CamKIIa-hTDP-43NLSm mouse model, ACI-6677 significantly limited the induction of phosphorylated TDP-43 (pTDP-43) inclusions. Strikingly, on the contralateral side, the mAb significantly prevented pTDP-43 inclusion appearance exemplifying blocking of the spreading process. Taken together, these data demonstrate for the first time that an immunotherapy targeting the protease-resistant amyloid core of TDP-43 has the potential to restrict spreading, substantially slowing or stopping progression of disease.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"156"},"PeriodicalIF":6.2,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11448013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-19DOI: 10.1186/s40478-024-01855-3
Tyler J. McCray, Logan M. Bedford, Stephanie J. Bissel, Bruce T. Lamb
Aging is the greatest known risk factor for most neurodegenerative diseases. Myelin degeneration is an early pathological indicator of these diseases and a normal part of aging; albeit, to a lesser extent. Despite this, little is known about the contribution of age-related myelin degeneration on neurodegenerative disease. Microglia participate in modulating white matter events from demyelination to remyelination, including regulation of (de)myelination by the microglial innate immune receptor triggering receptor expressed on myeloid cells 2 (TREM2). Here, we demonstrate Trem2-deficiency aggravates and accelerates age-related myelin degeneration in the striatum. We show TREM2 is necessary for remyelination by recruiting reparative glia and mediating signaling that promotes OPC differentiation/maturation. In response to demyelination, TREM2 is required for phagocytosis of large volumes of myelin debris. In addition to lysosomal regulation, we show TREM2 can modify the ER stress response, even prior to overt myelin debris, that prevents lipid accumulation and microglial dysfunction. These data support a role for Trem2-dependent interactions in age-related myelin degeneration and suggest a basis for how early dysfunctional microglia could contribute to disease pathology through insufficent repair, defective phagocytosis, and the ER stress response.
衰老是大多数神经退行性疾病的最大已知风险因素。髓鞘变性是这些疾病的早期病理指标，也是衰老的正常现象；尽管程度较轻。尽管如此，人们对与年龄相关的髓鞘变性对神经退行性疾病的影响知之甚少。小胶质细胞参与调节从脱髓鞘到再髓鞘化的白质事件，包括通过小胶质细胞先天性免疫受体触发髓系细胞上表达的受体2（TREM2）调节（脱）髓鞘化。在这里，我们证明了Trem2缺失会加重和加速纹状体中与年龄相关的髓鞘变性。我们发现 TREM2 是再髓鞘化所必需的，它能招募修复性神经胶质细胞并介导促进 OPC 分化/成熟的信号。在脱髓鞘反应中，TREM2 是吞噬大量髓鞘碎片所必需的。除了溶酶体调节外，我们还发现 TREM2 还能改变 ER 应激反应，甚至在出现明显的髓鞘碎片之前就能防止脂质积累和小胶质细胞功能障碍。这些数据支持特雷姆2依赖性相互作用在与年龄相关的髓鞘变性中的作用，并为早期功能失调的小胶质细胞如何通过不充分的修复、缺陷吞噬和ER应激反应导致疾病病理提供了依据。
{"title":"Trem2-deficiency aggravates and accelerates age-related myelin degeneration","authors":"Tyler J. McCray, Logan M. Bedford, Stephanie J. Bissel, Bruce T. Lamb","doi":"10.1186/s40478-024-01855-3","DOIUrl":"https://doi.org/10.1186/s40478-024-01855-3","url":null,"abstract":"Aging is the greatest known risk factor for most neurodegenerative diseases. Myelin degeneration is an early pathological indicator of these diseases and a normal part of aging; albeit, to a lesser extent. Despite this, little is known about the contribution of age-related myelin degeneration on neurodegenerative disease. Microglia participate in modulating white matter events from demyelination to remyelination, including regulation of (de)myelination by the microglial innate immune receptor triggering receptor expressed on myeloid cells 2 (TREM2). Here, we demonstrate Trem2-deficiency aggravates and accelerates age-related myelin degeneration in the striatum. We show TREM2 is necessary for remyelination by recruiting reparative glia and mediating signaling that promotes OPC differentiation/maturation. In response to demyelination, TREM2 is required for phagocytosis of large volumes of myelin debris. In addition to lysosomal regulation, we show TREM2 can modify the ER stress response, even prior to overt myelin debris, that prevents lipid accumulation and microglial dysfunction. These data support a role for Trem2-dependent interactions in age-related myelin degeneration and suggest a basis for how early dysfunctional microglia could contribute to disease pathology through insufficent repair, defective phagocytosis, and the ER stress response.","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"77 1","pages":""},"PeriodicalIF":7.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142269876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-19DOI: 10.1186/s40478-024-01843-7
Nathalie A. Lengacher, Julianna J. Tomlinson, Ann‑Kristin Jochum, Jonas Franz, Omar Hasan Ali, Lukas Flatz, Wolfram Jochum, Josef Penninger, Christine Stadelmann, John M. Woulfe, Michael G. Schlossmacher
<p><b>Correction: Acta Neuropathologica Communications (2024) 12:70</b> <b>https://doi.org/10.1186/s40478-024-01761-8</b></p><p>Following publication of the original article [1], in Fig. 3, B panel image “1” is incorrect. The incorrect section of the Fig. 3B and corrected version of full Fig. 3 is given below.</p><p>Incorrect Fig. 3, Panel B, Image 1:</p><figure><picture><source srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs40478-024-01843-7/MediaObjects/40478_2024_1843_Figa_HTML.jpg?as=webp" type="image/webp"/><img alt="figure a" aria-describedby="Figa" height="813" loading="lazy" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs40478-024-01843-7/MediaObjects/40478_2024_1843_Figa_HTML.jpg" width="685"/></picture></figure><p>Figure 3 and caption.</p><figure><figcaption><b data-test="figure-caption-text">Fig. 3</b></figcaption><picture><source srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs40478-024-01843-7/MediaObjects/40478_2024_1843_Fig3_HTML.png?as=webp" type="image/webp"/><img alt="figure 3" aria-describedby="Fig3" height="842" loading="lazy" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs40478-024-01843-7/MediaObjects/40478_2024_1843_Fig3_HTML.png" width="685"/></picture><p>Anti-phosphorylated α-synuclein reactivity in the anterior olfactory nucleus. <b>A</b> Example of immunohistochemical staining for p-αSyn in the human olfactory bulb, highlighting the AON from a person with Parkinson disease and related dementia [case #39]. Scale bars represent 100 μM. <b>B</b> Representative images of semi-quantitative scoring of pathology, ranging from 0 to 5, in the AON. Scale bars represent 50 μM. <b>C</b> Percentage of cases in each group that have a pathology score of 1 or higher. <b>D</b> Correlation between age and p-αSyn pathology scores in the control group (HCO and NCO combined) and COVID19 + cases. <b>E</b> Distribution of pathology scores for each group. Filled blue squares in <b>D</b> and <b>E</b> indicate COVID19 + cases suspected of having incidental LBD at autopsy; filled dark yellow diamond in <b>E</b> indicates AD case diagnosed with mixed pathology at autopsy, and filled green triangle indicates MSA case. Significance was determined using Kruskal–Wallis test with Dunn’s post-hoc (<b>E</b>), where **** indicates <i>p</i> ≤ 0.0001. Abbreviations for disease groups as in Fig. 1</p><span>Full size image</span><svg aria-hidden="true" focusable="false" height="16" role="img" width="16"><use xlink:href="#icon-eds-i-chevron-right-small" xmlns:xlink="http://www.w3.org/1999/xlink"></use></svg></figure><p>The original article has been corrected.</p><ol data-track-component="outbound reference" data-track-context="references section"><li data-counter="1."><p>Lengacher NA, Tomlinson JJ, Jochum AK et al (2024) Neuropathological assessment of the olfactory bulb and tract in individuals with COVID-19. Acta Neuropathol Commun 12:
如果文章的知识共享许可协议中没有包含相关材料，而您的使用意图又未得到法律法规的允许或超出了允许的使用范围，您需要直接从版权所有者处获得许可。要查看该许可的副本，请访问 http://creativecommons.org/licenses/by/4.0/。除非在数据的信用行中另有说明，否则知识共享公共领域专用免责声明 (http://creativecommons.org/publicdomain/zero/1.0/) 适用于本文提供的数据。转载与许可引用本文Lengacher, N.A., Tomlinson, J.J., Jochum, A. et al. Correction：对 COVID-19 患者嗅球和嗅束的神经病理学评估。Acta neuropathol commun 12, 153 (2024)。https://doi.org/10.1186/s40478-024-01843-7Download citationPublished: 19 September 2024DOI: https://doi.org/10.1186/s40478-024-01843-7Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative.
{"title":"Correction: Neuropathological assessment of the olfactory bulb and tract in individuals with COVID-19","authors":"Nathalie A. Lengacher, Julianna J. Tomlinson, Ann‑Kristin Jochum, Jonas Franz, Omar Hasan Ali, Lukas Flatz, Wolfram Jochum, Josef Penninger, Christine Stadelmann, John M. Woulfe, Michael G. Schlossmacher","doi":"10.1186/s40478-024-01843-7","DOIUrl":"https://doi.org/10.1186/s40478-024-01843-7","url":null,"abstract":"<p><b>Correction: Acta Neuropathologica Communications (2024) 12:70</b> <b>https://doi.org/10.1186/s40478-024-01761-8</b></p><p>Following publication of the original article [1], in Fig. 3, B panel image “1” is incorrect. The incorrect section of the Fig. 3B and corrected version of full Fig. 3 is given below.</p><p>Incorrect Fig. 3, Panel B, Image 1:</p><figure><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs40478-024-01843-7/MediaObjects/40478_2024_1843_Figa_HTML.jpg?as=webp\" type=\"image/webp\"/><img alt=\"figure a\" aria-describedby=\"Figa\" height=\"813\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs40478-024-01843-7/MediaObjects/40478_2024_1843_Figa_HTML.jpg\" width=\"685\"/></picture></figure><p>Figure 3 and caption.</p><figure><figcaption><b data-test=\"figure-caption-text\">Fig. 3</b></figcaption><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs40478-024-01843-7/MediaObjects/40478_2024_1843_Fig3_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure 3\" aria-describedby=\"Fig3\" height=\"842\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs40478-024-01843-7/MediaObjects/40478_2024_1843_Fig3_HTML.png\" width=\"685\"/></picture><p>Anti-phosphorylated α-synuclein reactivity in the anterior olfactory nucleus. <b>A</b> Example of immunohistochemical staining for p-αSyn in the human olfactory bulb, highlighting the AON from a person with Parkinson disease and related dementia [case #39]. Scale bars represent 100 μM. <b>B</b> Representative images of semi-quantitative scoring of pathology, ranging from 0 to 5, in the AON. Scale bars represent 50 μM. <b>C</b> Percentage of cases in each group that have a pathology score of 1 or higher. <b>D</b> Correlation between age and p-αSyn pathology scores in the control group (HCO and NCO combined) and COVID19 + cases. <b>E</b> Distribution of pathology scores for each group. Filled blue squares in <b>D</b> and <b>E</b> indicate COVID19 + cases suspected of having incidental LBD at autopsy; filled dark yellow diamond in <b>E</b> indicates AD case diagnosed with mixed pathology at autopsy, and filled green triangle indicates MSA case. Significance was determined using Kruskal–Wallis test with Dunn’s post-hoc (<b>E</b>), where **** indicates <i>p</i> ≤ 0.0001. Abbreviations for disease groups as in Fig. 1</p><span>Full size image</span><svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-chevron-right-small\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></figure><p>The original article has been corrected.</p><ol data-track-component=\"outbound reference\" data-track-context=\"references section\"><li data-counter=\"1.\"><p>Lengacher NA, Tomlinson JJ, Jochum AK et al (2024) Neuropathological assessment of the olfactory bulb and tract in individuals with COVID-19. Acta Neuropathol Commun 12:","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"20 1","pages":""},"PeriodicalIF":7.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18DOI: 10.1186/s40478-024-01857-1
Astrid T. van der Geest, Channa E. Jakobs, Tijana Ljubikj, Christiaan F. M. Huffels, Marta Cañizares Luna, Renata Vieira de Sá, Youri Adolfs, Marina de Wit, Daan H. Rutten, Marthe Kaal, Maria M. Zwartkruis, Mireia Carcolé, Ewout J. N. Groen, Elly M. Hol, Onur Basak, Adrian M. Isaacs, Henk-Jan Westeneng, Leonard H. van den Berg, Jan H. Veldink, Domino K. Schlegel, R. Jeroen Pasterkamp
A hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Human brain imaging and experimental studies indicate early changes in brain structure and connectivity in C9-ALS/FTD, even before symptom onset. Because these early disease phenotypes remain incompletely understood, we generated iPSC-derived cerebral organoid models from C9-ALS/FTD patients, presymptomatic C9ORF72-HRE (C9-HRE) carriers, and controls. Our work revealed the presence of all three C9-HRE-related molecular pathologies and developmental stage-dependent size phenotypes in cerebral organoids from C9-ALS/FTD patients. In addition, single-cell RNA sequencing identified changes in cell type abundance and distribution in C9-ALS/FTD organoids, including a reduction in the number of deep layer cortical neurons and the distribution of neural progenitors. Further, molecular and cellular analyses and patch-clamp electrophysiology detected various changes in synapse structure and function. Intriguingly, organoids from all presymptomatic C9-HRE carriers displayed C9-HRE molecular pathology, whereas the extent to which more downstream cellular defects, as found in C9-ALS/FTD models, were detected varied for the different presymptomatic C9-HRE cases. Together, these results unveil early changes in 3D human brain tissue organization and synaptic connectivity in C9-ALS/FTD that likely constitute initial pathologies crucial for understanding disease onset and the design of therapeutic strategies.
{"title":"Molecular pathology, developmental changes and synaptic dysfunction in (pre-) symptomatic human C9ORF72-ALS/FTD cerebral organoids","authors":"Astrid T. van der Geest, Channa E. Jakobs, Tijana Ljubikj, Christiaan F. M. Huffels, Marta Cañizares Luna, Renata Vieira de Sá, Youri Adolfs, Marina de Wit, Daan H. Rutten, Marthe Kaal, Maria M. Zwartkruis, Mireia Carcolé, Ewout J. N. Groen, Elly M. Hol, Onur Basak, Adrian M. Isaacs, Henk-Jan Westeneng, Leonard H. van den Berg, Jan H. Veldink, Domino K. Schlegel, R. Jeroen Pasterkamp","doi":"10.1186/s40478-024-01857-1","DOIUrl":"https://doi.org/10.1186/s40478-024-01857-1","url":null,"abstract":"A hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Human brain imaging and experimental studies indicate early changes in brain structure and connectivity in C9-ALS/FTD, even before symptom onset. Because these early disease phenotypes remain incompletely understood, we generated iPSC-derived cerebral organoid models from C9-ALS/FTD patients, presymptomatic C9ORF72-HRE (C9-HRE) carriers, and controls. Our work revealed the presence of all three C9-HRE-related molecular pathologies and developmental stage-dependent size phenotypes in cerebral organoids from C9-ALS/FTD patients. In addition, single-cell RNA sequencing identified changes in cell type abundance and distribution in C9-ALS/FTD organoids, including a reduction in the number of deep layer cortical neurons and the distribution of neural progenitors. Further, molecular and cellular analyses and patch-clamp electrophysiology detected various changes in synapse structure and function. Intriguingly, organoids from all presymptomatic C9-HRE carriers displayed C9-HRE molecular pathology, whereas the extent to which more downstream cellular defects, as found in C9-ALS/FTD models, were detected varied for the different presymptomatic C9-HRE cases. Together, these results unveil early changes in 3D human brain tissue organization and synaptic connectivity in C9-ALS/FTD that likely constitute initial pathologies crucial for understanding disease onset and the design of therapeutic strategies.","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"24 1","pages":""},"PeriodicalIF":7.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17DOI: 10.1186/s40478-024-01846-4
Richard A. Hickman, Alexandra M. Miller, Bridget M. Holle, Justin Jee, Si-Yang Liu, Dara Ross, Helena Yu, Gregory J. Riely, Christina Ombres, Alexandra N. Gewirtz, Anne S. Reiner, Subhiksha Nandakumar, Adam Price, Thomas J. Kaley, Maya S. Graham, Chad Vanderbilt, Satshil Rana, Katherine Hill, Kiana Chabot, Carl Campos, Khedoudja Nafa, Neerav Shukla, Matthias Karajannis, Bob Li, Michael Berger, Marc Ladanyi, Elena Pentsova, Adrienne Boire, A. Rose Brannon, Tejus Bale, Ingo K. Mellinghoff, Maria E. Arcila
The characterization of genetic alterations in tumor samples has become standard practice for many human cancers to achieve more precise disease classification and guide the selection of targeted therapies. Cerebrospinal fluid (CSF) can serve as a source of tumor DNA in patients with central nervous system (CNS) cancer. We performed comprehensive profiling of CSF circulating tumor DNA (ctDNA) in 711 patients using an FDA-authorized platform (MSK-IMPACT™) in a hospital laboratory. We identified genetic alterations in 489/922 (53.0%) CSF samples with clinically documented CNS tumors. None of 85 CSF samples from patients without CNS tumors had detectable ctDNA. The distribution of clinically actionable somatic alterations was consistent with tumor-type specific alterations across the AACR GENIE cohort. Repeated CSF ctDNA examinations from the same patients identified clonal evolution and emergence of resistance mechanisms. ctDNA detection was associated with shortened overall survival following CSF collection. Next-generation sequencing of CSF, collected through a minimally invasive lumbar puncture in a routine hospital setting, provides clinically actionable cancer genotype information in a large fraction of patients with CNS tumors.
{"title":"Real-world experience with circulating tumor DNA in cerebrospinal fluid from patients with central nervous system tumors","authors":"Richard A. Hickman, Alexandra M. Miller, Bridget M. Holle, Justin Jee, Si-Yang Liu, Dara Ross, Helena Yu, Gregory J. Riely, Christina Ombres, Alexandra N. Gewirtz, Anne S. Reiner, Subhiksha Nandakumar, Adam Price, Thomas J. Kaley, Maya S. Graham, Chad Vanderbilt, Satshil Rana, Katherine Hill, Kiana Chabot, Carl Campos, Khedoudja Nafa, Neerav Shukla, Matthias Karajannis, Bob Li, Michael Berger, Marc Ladanyi, Elena Pentsova, Adrienne Boire, A. Rose Brannon, Tejus Bale, Ingo K. Mellinghoff, Maria E. Arcila","doi":"10.1186/s40478-024-01846-4","DOIUrl":"https://doi.org/10.1186/s40478-024-01846-4","url":null,"abstract":"The characterization of genetic alterations in tumor samples has become standard practice for many human cancers to achieve more precise disease classification and guide the selection of targeted therapies. Cerebrospinal fluid (CSF) can serve as a source of tumor DNA in patients with central nervous system (CNS) cancer. We performed comprehensive profiling of CSF circulating tumor DNA (ctDNA) in 711 patients using an FDA-authorized platform (MSK-IMPACT™) in a hospital laboratory. We identified genetic alterations in 489/922 (53.0%) CSF samples with clinically documented CNS tumors. None of 85 CSF samples from patients without CNS tumors had detectable ctDNA. The distribution of clinically actionable somatic alterations was consistent with tumor-type specific alterations across the AACR GENIE cohort. Repeated CSF ctDNA examinations from the same patients identified clonal evolution and emergence of resistance mechanisms. ctDNA detection was associated with shortened overall survival following CSF collection. Next-generation sequencing of CSF, collected through a minimally invasive lumbar puncture in a routine hospital setting, provides clinically actionable cancer genotype information in a large fraction of patients with CNS tumors.","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"16 1","pages":""},"PeriodicalIF":7.1,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Glaucoma is a leading cause of blindness, affecting retinal ganglion cells (RGCs) and their axons. By 2040, it is likely to affect 110 million people. Neuroinflammation, specifically through the release of proinflammatory cytokines by M1 microglial cells, plays a crucial role in glaucoma progression. Indeed, in post-mortem human studies, pre-clinical models, and ex-vivo models, RGC degeneration has been consistently shown to be linked to inflammation in response to cell death and tissue damage. Recently, Rho kinase inhibitors (ROCKis) have emerged as potential therapies for neuroinflammatory and neurodegenerative diseases. This study aimed to investigate the potential effects of three ROCKis (Y-27632, Y-33075, and H-1152) on retinal ganglion cell (RGC) loss and retinal neuroinflammation using an ex-vivo retinal explant model. Rat retinal explants underwent optic nerve axotomy and were treated with Y-27632, Y-33075, or H-1152. The neuroprotective effects on RGCs were evaluated using immunofluorescence and Brn3a-specific markers. Reactive glia and microglial activation were studied by GFAP, CD68, and Iba1 staining. Flow cytometry was used to quantify day ex-vivo 4 (DEV 4) microglial proliferation and M1 activation by measuring the number of CD11b+, CD68+, and CD11b+/CD68+ cells after treatment with control solvent or Y-33075. The modulation of gene expression was measured by RNA-seq analysis on control and Y-33075-treated explants and glial and pro-inflammatory cytokine gene expression was validated by RT-qPCR. Y-27632 and H-1152 did not significantly protect RGCs. By contrast, at DEV 4, 50 µM Y-33075 significantly increased RGC survival. Immunohistology showed a reduced number of Iba1+/CD68+ cells and limited astrogliosis with Y-33075 treatment. Flow cytometry confirmed lower CD11b+, CD68+, and CD11b+/CD68+ cell numbers in the Y-33075 group. RNA-seq showed Y-33075 inhibited the expression of M1 microglial markers (Tnfα, Il-1β, Nos2) and glial markers (Gfap, Itgam, Cd68) and to reduce apoptosis, ferroptosis, inflammasome formation, complement activation, TLR pathway activation, and P2rx7 and Gpr84 gene expression. Conversely, Y-33075 upregulated RGC-specific markers, neurofilament formation, and neurotransmitter regulator expression, consistent with its neuroprotective effects. Y-33075 demonstrates marked neuroprotective and anti-inflammatory effects, surpassing the other tested ROCKis (Y-27632 and H-1152) in preventing RGC death and reducing microglial inflammatory responses. These findings highlight its potential as a therapeutic option for glaucoma.
{"title":"Evaluation of Rho kinase inhibitor effects on neuroprotection and neuroinflammation in an ex-vivo retinal explant model","authors":"Élodie Reboussin, Paul Bastelica, Ilyes Benmessabih, Arnaud Cordovilla, Cécile Delarasse, Annabelle Réaux-Le Goazigo, Françoise Brignole-Baudouin, Céline Olmière, Christophe Baudouin, Juliette Buffault, Stéphane Mélik Parsadaniantz","doi":"10.1186/s40478-024-01859-z","DOIUrl":"https://doi.org/10.1186/s40478-024-01859-z","url":null,"abstract":"Glaucoma is a leading cause of blindness, affecting retinal ganglion cells (RGCs) and their axons. By 2040, it is likely to affect 110 million people. Neuroinflammation, specifically through the release of proinflammatory cytokines by M1 microglial cells, plays a crucial role in glaucoma progression. Indeed, in post-mortem human studies, pre-clinical models, and ex-vivo models, RGC degeneration has been consistently shown to be linked to inflammation in response to cell death and tissue damage. Recently, Rho kinase inhibitors (ROCKis) have emerged as potential therapies for neuroinflammatory and neurodegenerative diseases. This study aimed to investigate the potential effects of three ROCKis (Y-27632, Y-33075, and H-1152) on retinal ganglion cell (RGC) loss and retinal neuroinflammation using an ex-vivo retinal explant model. Rat retinal explants underwent optic nerve axotomy and were treated with Y-27632, Y-33075, or H-1152. The neuroprotective effects on RGCs were evaluated using immunofluorescence and Brn3a-specific markers. Reactive glia and microglial activation were studied by GFAP, CD68, and Iba1 staining. Flow cytometry was used to quantify day ex-vivo 4 (DEV 4) microglial proliferation and M1 activation by measuring the number of CD11b+, CD68+, and CD11b+/CD68+ cells after treatment with control solvent or Y-33075. The modulation of gene expression was measured by RNA-seq analysis on control and Y-33075-treated explants and glial and pro-inflammatory cytokine gene expression was validated by RT-qPCR. Y-27632 and H-1152 did not significantly protect RGCs. By contrast, at DEV 4, 50 µM Y-33075 significantly increased RGC survival. Immunohistology showed a reduced number of Iba1+/CD68+ cells and limited astrogliosis with Y-33075 treatment. Flow cytometry confirmed lower CD11b+, CD68+, and CD11b+/CD68+ cell numbers in the Y-33075 group. RNA-seq showed Y-33075 inhibited the expression of M1 microglial markers (Tnfα, Il-1β, Nos2) and glial markers (Gfap, Itgam, Cd68) and to reduce apoptosis, ferroptosis, inflammasome formation, complement activation, TLR pathway activation, and P2rx7 and Gpr84 gene expression. Conversely, Y-33075 upregulated RGC-specific markers, neurofilament formation, and neurotransmitter regulator expression, consistent with its neuroprotective effects. Y-33075 demonstrates marked neuroprotective and anti-inflammatory effects, surpassing the other tested ROCKis (Y-27632 and H-1152) in preventing RGC death and reducing microglial inflammatory responses. These findings highlight its potential as a therapeutic option for glaucoma.","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"30 1","pages":""},"PeriodicalIF":7.1,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.1186/s40478-024-01858-0
Yu Meng Wang, Jing Yan, Sarah K. Williams, Richard Fairless, Hilmar Bading
Motor neuron loss is well recognized in amyotrophic lateral sclerosis (ALS), but research on retinal ganglion cells (RGCs) is limited. Ocular symptoms are generally not considered classic ALS symptoms, although RGCs and spinal motor neurons share certain cell pathologies, including hallmark signs of glutamate neurotoxicity, which may be triggered by activation of extrasynaptic NMDA receptors (NMDARs). To explore potential novel strategies to prevent ALS-associated death of RGCs, we utilized inhibition of the TwinF interface, a new pharmacological principle that detoxifies extrasynaptic NMDARs by disrupting the NMDAR/TRPM4 death signaling complex. Using the ALS mouse model SOD1G93A, we found that the small molecule TwinF interface inhibitor FP802 prevents the loss of RGCs, improves pattern electroretinogram (pERG) performance, increases the retinal expression of Bdnf, and restores the retinal expression of the immediate early genes, Inhibin beta A and Npas4. Thus, FP802 not only prevents, as recently described, death of spinal motor neurons in SOD1G93A mice, but it also mitigates ALS-associated retinal damage. TwinF interface inhibitors have great potential for alleviating neuro-ophthalmologic symptoms in ALS patients and offer a promising new avenue for therapeutic intervention.
肌萎缩性脊髓侧索硬化症（ALS）的运动神经元缺失是公认的，但对视网膜神经节细胞（RGC）的研究却很有限。眼部症状通常不被认为是典型的渐冻症症状，尽管RGCs和脊髓运动神经元具有某些共同的细胞病理特征，包括谷氨酸神经毒性的标志性症状，这可能是由突触外NMDA受体（NMDARs）激活引发的。为了探索预防与渐冻症相关的 RGCs 死亡的潜在新策略，我们利用了抑制 TwinF 接口的方法，这是一种新的药理学原理，通过破坏 NMDAR/TRPM4 死亡信号复合物来解毒突触外 NMDAR。通过 ALS 小鼠模型 SOD1G93A，我们发现小分子 TwinF 接口抑制剂 FP802 可以防止 RGC 的丧失，改善模式视网膜电图（pERG）表现，增加视网膜中 Bdnf 的表达，并恢复视网膜中即时早期基因 Inhibin beta A 和 Npas4 的表达。因此，FP802 不仅能防止最近描述的 SOD1G93A 小鼠脊髓运动神经元的死亡，还能减轻 ALS 相关的视网膜损伤。双F界面抑制剂在缓解 ALS 患者的神经眼科症状方面具有巨大潜力，为治疗干预提供了一条前景广阔的新途径。
{"title":"TwinF interface inhibitor FP802 prevents retinal ganglion cell loss in a mouse model of amyotrophic lateral sclerosis","authors":"Yu Meng Wang, Jing Yan, Sarah K. Williams, Richard Fairless, Hilmar Bading","doi":"10.1186/s40478-024-01858-0","DOIUrl":"https://doi.org/10.1186/s40478-024-01858-0","url":null,"abstract":"Motor neuron loss is well recognized in amyotrophic lateral sclerosis (ALS), but research on retinal ganglion cells (RGCs) is limited. Ocular symptoms are generally not considered classic ALS symptoms, although RGCs and spinal motor neurons share certain cell pathologies, including hallmark signs of glutamate neurotoxicity, which may be triggered by activation of extrasynaptic NMDA receptors (NMDARs). To explore potential novel strategies to prevent ALS-associated death of RGCs, we utilized inhibition of the TwinF interface, a new pharmacological principle that detoxifies extrasynaptic NMDARs by disrupting the NMDAR/TRPM4 death signaling complex. Using the ALS mouse model SOD1G93A, we found that the small molecule TwinF interface inhibitor FP802 prevents the loss of RGCs, improves pattern electroretinogram (pERG) performance, increases the retinal expression of Bdnf, and restores the retinal expression of the immediate early genes, Inhibin beta A and Npas4. Thus, FP802 not only prevents, as recently described, death of spinal motor neurons in SOD1G93A mice, but it also mitigates ALS-associated retinal damage. TwinF interface inhibitors have great potential for alleviating neuro-ophthalmologic symptoms in ALS patients and offer a promising new avenue for therapeutic intervention.","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"183 1","pages":""},"PeriodicalIF":7.1,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1186/s40478-024-01860-6
Olga Kim, Zach Sergi, Guangyang Yu, Kazutoshi Yamamoto, Martha Quezado, Zied Abdullaev, Danel R. Crooks, Shun Kishimoto, Qi Li, Peng Lu, Burchelle Blackman, Thorkell Andresson, Xiaolin Wu, Bao Tran, Jun S. Wei, Wei Zhang, Meili Zhang, Hua Song, Javed Khan, Murali C. Krishna, Jeffrey R. Brender, Jing Wu
Malignant transformation (MT) is commonly seen in IDH-mutant gliomas. There has been a growing research interest in revealing its underlying mechanisms and intervening prior to MT at the early stages of the transforming process. Here we established a unique pair of matched 3D cell models: 403L, derived from a low-grade glioma (LGG), and 403H, derived from a high-grade glioma (HGG), by utilizing IDH-mutant astrocytoma samples from the same patient when the tumor was diagnosed as WHO grade 2 (tumor mutational burden (TMB) of 3.96/Mb) and later as grade 4 (TMB of 70.07/Mb), respectively. Both cell models were authenticated to a patient’s sample retaining endogenous expression of IDH1 R132H. DNA methylation profiles of the parental tumors referred to LGG and HGG IDH-mutant glioma clusters. The immunopositivity of SOX2, NESTIN, GFAP, OLIG2, and beta 3-Tubulin suggested the multilineage potential of both models. 403H was more prompt to cell invasion and developed infiltrative HGG in vivo. The differentially expressed genes (DEGs) from the RNA sequencing analysis revealed the tumor invasion and aggressiveness related genes exclusively upregulated in the 403H model. Pathway analysis showcased an enrichment of genes associated with epithelial-mesenchymal transition (EMT) and Notch signaling pathways in 403H and 403L, respectively. Mass spectrometry-based targeted metabolomics and hyperpolarized (HP) 1-13C pyruvate in-cell NMR analyses demonstrated significant alterations in the TCA cycle and fatty acid metabolism. Citrate, glutamine, and 2-HG levels were significantly higher in 403H. To our knowledge, this is the first report describing the development of a matched pair of 3D patient-derived cell models representative of MT and temozolomide (TMZ)-induced hypermutator phenotype (HMP) in IDH-mutant glioma, providing insights into genetic and metabolic changes during MT/HMP. This novel in vitro model allows further investigation of the mechanisms of MT at the cellular level.
{"title":"A patient-derived cell model for malignant transformation in IDH-mutant glioma","authors":"Olga Kim, Zach Sergi, Guangyang Yu, Kazutoshi Yamamoto, Martha Quezado, Zied Abdullaev, Danel R. Crooks, Shun Kishimoto, Qi Li, Peng Lu, Burchelle Blackman, Thorkell Andresson, Xiaolin Wu, Bao Tran, Jun S. Wei, Wei Zhang, Meili Zhang, Hua Song, Javed Khan, Murali C. Krishna, Jeffrey R. Brender, Jing Wu","doi":"10.1186/s40478-024-01860-6","DOIUrl":"https://doi.org/10.1186/s40478-024-01860-6","url":null,"abstract":"Malignant transformation (MT) is commonly seen in IDH-mutant gliomas. There has been a growing research interest in revealing its underlying mechanisms and intervening prior to MT at the early stages of the transforming process. Here we established a unique pair of matched 3D cell models: 403L, derived from a low-grade glioma (LGG), and 403H, derived from a high-grade glioma (HGG), by utilizing IDH-mutant astrocytoma samples from the same patient when the tumor was diagnosed as WHO grade 2 (tumor mutational burden (TMB) of 3.96/Mb) and later as grade 4 (TMB of 70.07/Mb), respectively. Both cell models were authenticated to a patient’s sample retaining endogenous expression of IDH1 R132H. DNA methylation profiles of the parental tumors referred to LGG and HGG IDH-mutant glioma clusters. The immunopositivity of SOX2, NESTIN, GFAP, OLIG2, and beta 3-Tubulin suggested the multilineage potential of both models. 403H was more prompt to cell invasion and developed infiltrative HGG in vivo. The differentially expressed genes (DEGs) from the RNA sequencing analysis revealed the tumor invasion and aggressiveness related genes exclusively upregulated in the 403H model. Pathway analysis showcased an enrichment of genes associated with epithelial-mesenchymal transition (EMT) and Notch signaling pathways in 403H and 403L, respectively. Mass spectrometry-based targeted metabolomics and hyperpolarized (HP) 1-13C pyruvate in-cell NMR analyses demonstrated significant alterations in the TCA cycle and fatty acid metabolism. Citrate, glutamine, and 2-HG levels were significantly higher in 403H. To our knowledge, this is the first report describing the development of a matched pair of 3D patient-derived cell models representative of MT and temozolomide (TMZ)-induced hypermutator phenotype (HMP) in IDH-mutant glioma, providing insights into genetic and metabolic changes during MT/HMP. This novel in vitro model allows further investigation of the mechanisms of MT at the cellular level. ","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"437 1","pages":""},"PeriodicalIF":7.1,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1186/s40478-024-01856-2
Nan Lian, Fangzhou Li, Cheng Zhou, Yan Yin, Yi Kang, Kaiteng Luo, Su Lui, Tao Li, Peilin Lu
Maladaptive changes of metabolic patterns in the lumbar dorsal root ganglion (DRG) are critical for nociceptive hypersensitivity genesis. The accumulation of branched-chain amino acids (BCAAs) in DRG has been implicated in mechanical allodynia and thermal hyperalgesia, but the exact mechanism is not fully understood. This study aimed to explore how BCAA catabolism in DRG modulates pain sensitization. Wildtype male mice were fed a high-fat diet (HFD) for 8 weeks. Adult PP2Cmfl/fl mice of both sexes were intrathecally injected with pAAV9-hSyn-Cre to delete the mitochondrial targeted 2 C-type serine/threonine protein phosphatase (PP2Cm) in DRG neurons. Here, we reported that BCAA catabolism was impaired in the lumbar 4–5 (L4-L5) DRGs of mice fed a high-fat diet (HFD). Conditional deletion of PP2Cm in DRG neurons led to mechanical allodynia, heat and cold hyperalgesia. Mechanistically, the genetic knockout of PP2Cm resulted in the upregulation of C-C chemokine ligand 5/C-C chemokine receptor 5 (CCL5/CCR5) axis and an increase in transient receptor potential ankyrin 1 (TRPA1) expression. Blocking the CCL5/CCR5 signaling or TRPA1 alleviated pain behaviors induced by PP2Cm deletion. Thus, targeting BCAA catabolism in DRG neurons may be a potential management strategy for pain sensitization.
{"title":"Protein phosphatase 2Cm-regulated branched-chain amino acid catabolic defect in dorsal root ganglion neurons drives pain sensitization","authors":"Nan Lian, Fangzhou Li, Cheng Zhou, Yan Yin, Yi Kang, Kaiteng Luo, Su Lui, Tao Li, Peilin Lu","doi":"10.1186/s40478-024-01856-2","DOIUrl":"https://doi.org/10.1186/s40478-024-01856-2","url":null,"abstract":"Maladaptive changes of metabolic patterns in the lumbar dorsal root ganglion (DRG) are critical for nociceptive hypersensitivity genesis. The accumulation of branched-chain amino acids (BCAAs) in DRG has been implicated in mechanical allodynia and thermal hyperalgesia, but the exact mechanism is not fully understood. This study aimed to explore how BCAA catabolism in DRG modulates pain sensitization. Wildtype male mice were fed a high-fat diet (HFD) for 8 weeks. Adult PP2Cmfl/fl mice of both sexes were intrathecally injected with pAAV9-hSyn-Cre to delete the mitochondrial targeted 2 C-type serine/threonine protein phosphatase (PP2Cm) in DRG neurons. Here, we reported that BCAA catabolism was impaired in the lumbar 4–5 (L4-L5) DRGs of mice fed a high-fat diet (HFD). Conditional deletion of PP2Cm in DRG neurons led to mechanical allodynia, heat and cold hyperalgesia. Mechanistically, the genetic knockout of PP2Cm resulted in the upregulation of C-C chemokine ligand 5/C-C chemokine receptor 5 (CCL5/CCR5) axis and an increase in transient receptor potential ankyrin 1 (TRPA1) expression. Blocking the CCL5/CCR5 signaling or TRPA1 alleviated pain behaviors induced by PP2Cm deletion. Thus, targeting BCAA catabolism in DRG neurons may be a potential management strategy for pain sensitization.","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"22 1","pages":""},"PeriodicalIF":7.1,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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