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":"10.1007/s00401-024-02739-5","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"147 1","pages":""},"PeriodicalIF":9.3,"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":"10.1007/s00401-024-02741-x","url":null,"abstract":"<div><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></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"147 1","pages":""},"PeriodicalIF":9.3,"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":"10.1007/s00401-024-02736-8","url":null,"abstract":"<div><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></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"147 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02736-8.pdf","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":"OA","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":"<div><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). <i>CHCHD2</i> 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 <i>CHCHD2</i> 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 <i>CHCHD2</i> in maintaining mitochondrial health and its implications for the disease.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"147 1","pages":""},"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":"147 1","pages":""},"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":"10.1007/s00401-024-02733-x","url":null,"abstract":"<div><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></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"147 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02733-x.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-08DOI: 10.1007/s00401-024-02717-x
Klaus Schmierer, Hans Lassmann
{"title":"The shoulders we keep standing on: remembering Otto Marburg, a big brain in neurology and multiple sclerosis, at 150","authors":"Klaus Schmierer, Hans Lassmann","doi":"10.1007/s00401-024-02717-x","DOIUrl":"10.1007/s00401-024-02717-x","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"147 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140875540","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 : 2024-05-07DOI: 10.1007/s00401-024-02737-7
Mirte Scheper, Frederik N. F. Sørensen, Gabriele Ruffolo, Alessandro Gaeta, Lilian J. Lissner, Jasper J. Anink, Irina Korshunova, Floor E. Jansen, Kate Riney, Wim van Hecke, Angelika Mühlebner, Konstantin Khodosevich, Dirk Schubert, Eleonora Palma, James D. Mills, Eleonora Aronica
GABAergic interneurons play a critical role in maintaining neural circuit balance, excitation–inhibition regulation, and cognitive function modulation. In tuberous sclerosis complex (TSC), GABAergic neuron dysfunction contributes to disrupted network activity and associated neurological symptoms, assumingly in a cell type-specific manner. This GABAergic centric study focuses on identifying specific interneuron subpopulations within TSC, emphasizing the unique characteristics of medial ganglionic eminence (MGE)- and caudal ganglionic eminence (CGE)-derived interneurons. Using single-nuclei RNA sequencing in TSC patient material, we identify somatostatin-expressing (SST+) interneurons as a unique and immature subpopulation in TSC. The disrupted maturation of SST+ interneurons may undergo an incomplete switch from excitatory to inhibitory GABAergic signaling during development, resulting in reduced inhibitory properties. Notably, this study reveals markers of immaturity specifically in SST+ interneurons, including an abnormal NKCC1/KCC2 ratio, indicating an imbalance in chloride homeostasis crucial for the postsynaptic consequences of GABAergic signaling as well as the downregulation of GABAA receptor subunits, GABRA1, and upregulation of GABRA2. Further exploration of SST+ interneurons revealed altered localization patterns of SST+ interneurons in TSC brain tissue, concentrated in deeper cortical layers, possibly linked to cortical dyslamination. In the epilepsy context, our research underscores the diverse cell type-specific roles of GABAergic interneurons in shaping seizures, advocating for precise therapeutic considerations. Moreover, this study illuminates the potential contribution of SST+ interneurons to TSC pathophysiology, offering insights for targeted therapeutic interventions.
{"title":"Impaired GABAergic regulation and developmental immaturity in interneurons derived from the medial ganglionic eminence in the tuberous sclerosis complex","authors":"Mirte Scheper, Frederik N. F. Sørensen, Gabriele Ruffolo, Alessandro Gaeta, Lilian J. Lissner, Jasper J. Anink, Irina Korshunova, Floor E. Jansen, Kate Riney, Wim van Hecke, Angelika Mühlebner, Konstantin Khodosevich, Dirk Schubert, Eleonora Palma, James D. Mills, Eleonora Aronica","doi":"10.1007/s00401-024-02737-7","DOIUrl":"10.1007/s00401-024-02737-7","url":null,"abstract":"<div><p>GABAergic interneurons play a critical role in maintaining neural circuit balance, excitation–inhibition regulation, and cognitive function modulation. In tuberous sclerosis complex (TSC), GABAergic neuron dysfunction contributes to disrupted network activity and associated neurological symptoms, assumingly in a cell type-specific manner. This GABAergic centric study focuses on identifying specific interneuron subpopulations within TSC, emphasizing the unique characteristics of medial ganglionic eminence (MGE)- and caudal ganglionic eminence (CGE)-derived interneurons. Using single-nuclei RNA sequencing in TSC patient material, we identify somatostatin-expressing (SST+) interneurons as a unique and immature subpopulation in TSC. The disrupted maturation of SST+ interneurons may undergo an incomplete switch from excitatory to inhibitory GABAergic signaling during development, resulting in reduced inhibitory properties. Notably, this study reveals markers of immaturity specifically in SST+ interneurons, including an abnormal <i>NKCC1/KCC2</i> ratio, indicating an imbalance in chloride homeostasis crucial for the postsynaptic consequences of GABAergic signaling as well as the downregulation of GABA<sub>A</sub> receptor subunits, <i>GABRA1</i>, and upregulation of <i>GABRA2.</i> Further exploration of SST+ interneurons revealed altered localization patterns of SST+ interneurons in TSC brain tissue, concentrated in deeper cortical layers, possibly linked to cortical dyslamination. In the epilepsy context, our research underscores the diverse cell type-specific roles of GABAergic interneurons in shaping seizures, advocating for precise therapeutic considerations. Moreover, this study illuminates the potential contribution of SST+ interneurons to TSC pathophysiology, offering insights for targeted therapeutic interventions.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"147 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02737-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140875157","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 : 2024-05-05DOI: 10.1007/s00401-024-02735-9
Hailong Song, Alexandra Tomasevich, Andrew Paolini, Kevin D. Browne, Kathryn L. Wofford, Brian Kelley, Eashwar Kantemneni, Justin Kennedy, Yue Qiu, Andrea L. C. Schneider, Jean-Pierre Dolle, D. Kacy Cullen, Douglas H. Smith
Although human females appear be at a higher risk of concussion and suffer worse outcomes than males, underlying mechanisms remain unclear. With increasing recognition that damage to white matter axons is a key pathologic substrate of concussion, we used a clinically relevant swine model of concussion to explore potential sex differences in the extent of axonal pathologies. At 24 h post-injury, female swine displayed a greater number of swollen axonal profiles and more widespread loss of axonal sodium channels than males. Axon degeneration for both sexes appeared to be related to individual axon architecture, reflected by a selective loss of small caliber axons after concussion. However, female brains had a higher percentage of small caliber axons, leading to more extensive axon loss after injury compared to males. Accordingly, sexual dimorphism in axonal size is associated with more extensive axonal pathology in females after concussion, which may contribute to worse outcomes.
{"title":"Sex differences in the extent of acute axonal pathologies after experimental concussion","authors":"Hailong Song, Alexandra Tomasevich, Andrew Paolini, Kevin D. Browne, Kathryn L. Wofford, Brian Kelley, Eashwar Kantemneni, Justin Kennedy, Yue Qiu, Andrea L. C. Schneider, Jean-Pierre Dolle, D. Kacy Cullen, Douglas H. Smith","doi":"10.1007/s00401-024-02735-9","DOIUrl":"10.1007/s00401-024-02735-9","url":null,"abstract":"<div><p>Although human females appear be at a higher risk of concussion and suffer worse outcomes than males, underlying mechanisms remain unclear. With increasing recognition that damage to white matter axons is a key pathologic substrate of concussion, we used a clinically relevant swine model of concussion to explore potential sex differences in the extent of axonal pathologies. At 24 h post-injury, female swine displayed a greater number of swollen axonal profiles and more widespread loss of axonal sodium channels than males. Axon degeneration for both sexes appeared to be related to individual axon architecture, reflected by a selective loss of small caliber axons after concussion. However, female brains had a higher percentage of small caliber axons, leading to more extensive axon loss after injury compared to males. Accordingly, sexual dimorphism in axonal size is associated with more extensive axonal pathology in females after concussion, which may contribute to worse outcomes.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"147 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02735-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140845233","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 : 2024-05-02DOI: 10.1007/s00401-024-02727-9
Nurun N. Fancy, Amy M. Smith, Alessia Caramello, Stergios Tsartsalis, Karen Davey, Robert C. J. Muirhead, Aisling McGarry, Marion H. Jenkyns, Eleonore Schneegans, Vicky Chau, Michael Thomas, Sam Boulger, To Ka Dorcas Cheung, Emily Adair, Marianna Papageorgopoulou, Nanet Willumsen, Combiz Khozoie, Diego Gomez-Nicola, Johanna S. Jackson, Paul M. Matthews
Aging is associated with cell senescence and is the major risk factor for AD. We characterized premature cell senescence in postmortem brains from non-diseased controls (NDC) and donors with Alzheimer’s disease (AD) using imaging mass cytometry (IMC) and single nuclear RNA (snRNA) sequencing (> 200,000 nuclei). We found increases in numbers of glia immunostaining for galactosidase beta (> fourfold) and p16INK4A (up to twofold) with AD relative to NDC. Increased glial expression of genes related to senescence was associated with greater β-amyloid load. Prematurely senescent microglia downregulated phagocytic pathways suggesting reduced capacity for β-amyloid clearance. Gene set enrichment and pseudo-time trajectories described extensive DNA double-strand breaks (DSBs), mitochondrial dysfunction and ER stress associated with increased β-amyloid leading to premature senescence in microglia. We replicated these observations with independent AD snRNA-seq datasets. Our results describe a burden of senescent glia with AD that is sufficiently high to contribute to disease progression. These findings support the hypothesis that microglia are a primary target for senolytic treatments in AD.
{"title":"Characterisation of premature cell senescence in Alzheimer’s disease using single nuclear transcriptomics","authors":"Nurun N. Fancy, Amy M. Smith, Alessia Caramello, Stergios Tsartsalis, Karen Davey, Robert C. J. Muirhead, Aisling McGarry, Marion H. Jenkyns, Eleonore Schneegans, Vicky Chau, Michael Thomas, Sam Boulger, To Ka Dorcas Cheung, Emily Adair, Marianna Papageorgopoulou, Nanet Willumsen, Combiz Khozoie, Diego Gomez-Nicola, Johanna S. Jackson, Paul M. Matthews","doi":"10.1007/s00401-024-02727-9","DOIUrl":"10.1007/s00401-024-02727-9","url":null,"abstract":"<div><p>Aging is associated with cell senescence and is the major risk factor for AD. We characterized premature cell senescence in postmortem brains from non-diseased controls (NDC) and donors with Alzheimer’s disease (AD) using imaging mass cytometry (IMC) and single nuclear RNA (snRNA) sequencing (> 200,000 nuclei). We found increases in numbers of glia immunostaining for galactosidase beta (> fourfold) and p16<sup>INK4A</sup> (up to twofold) with AD relative to NDC. Increased glial expression of genes related to senescence was associated with greater β-amyloid load. Prematurely senescent microglia downregulated phagocytic pathways suggesting reduced capacity for β-amyloid clearance. Gene set enrichment and pseudo-time trajectories described extensive DNA double-strand breaks (DSBs), mitochondrial dysfunction and ER stress associated with increased β-amyloid leading to premature senescence in microglia. We replicated these observations with independent AD snRNA-seq datasets. Our results describe a burden of senescent glia with AD that is sufficiently high to contribute to disease progression. These findings support the hypothesis that microglia are a primary target for senolytic treatments in AD.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"147 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02727-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140819274","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}