Pub Date : 2024-11-06DOI: 10.1186/s40478-024-01869-x
Ilah Shin, Yae Won Park, Yongsik Sim, Seo Hee Choi, Sung Soo Ahn, Jong Hee Chang, Se Hoon Kim, Seung-Koo Lee, Rajan Jain
{"title":"Correction: Revisiting gliomatosis cerebri in adult-type diffuse gliomas: a comprehensive imaging, genomic and clinical analysis.","authors":"Ilah Shin, Yae Won Park, Yongsik Sim, Seo Hee Choi, Sung Soo Ahn, Jong Hee Chang, Se Hoon Kim, Seung-Koo Lee, Rajan Jain","doi":"10.1186/s40478-024-01869-x","DOIUrl":"10.1186/s40478-024-01869-x","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581642","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 : 2024-11-06DOI: 10.1186/s40478-024-01877-x
Elena Niccolai, Leandro Di Gloria, Maria Chiara Trolese, Paola Fabbrizio, Simone Baldi, Giulia Nannini, Cassandra Margotta, Claudia Nastasi, Matteo Ramazzotti, Gianluca Bartolucci, Caterina Bendotti, Giovanni Nardo, Amedeo Amdei
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons, with genetic and environmental factors contributing to its complex pathogenesis. Dysregulated immune responses and altered energetic metabolism are key features, with emerging evidence implicating the gut microbiota (GM) in disease progression. We investigated the interplay among genetic background, GM composition, metabolism, and immune response in two distinct ALS mouse models: 129Sv_G93A and C57Ola_G93A, representing rapid and slow disease progression, respectively.Using 16 S rRNA sequencing and fecal metabolite analysis, we characterized the GM composition and metabolite profiles in non-transgenic (Ntg) and SOD1G93A mutant mice of both strains. Our results revealed strain-specific differences in GM composition and functions, particularly in the abundance of taxa belonging to Erysipelotrichaceae and the levels of short and medium-chain fatty acids in fecal samples. The SOD1 mutation induces significant shifts in GM colonization in both strains, with C57Ola_G93A mice showing changes resembling those in 129 Sv mice, potentially affecting disease pathogenesis. ALS symptom progression does not significantly alter microbiota composition, suggesting stability.Additionally, we assessed systemic immunity and inflammatory responses revealing strain-specific differences in immune cell populations and cytokine levels.Our findings underscore the substantial influence of genetic background on GM composition, metabolism, and immune response in ALS mouse models. These strain-specific variations may contribute to differences in disease susceptibility and progression rates. Further elucidating the mechanisms underlying these interactions could offer novel insights into ALS pathogenesis and potential therapeutic targets.
肌萎缩侧索硬化症(ALS)是一种以运动神经元进行性丧失为特征的破坏性神经退行性疾病,其复杂的发病机制与遗传和环境因素有关。免疫反应失调和能量代谢改变是其主要特征,有新的证据表明肠道微生物群(GM)与疾病进展有关。我们在两种不同的 ALS 小鼠模型中研究了遗传背景、GM 组成、新陈代谢和免疫反应之间的相互作用:利用 16 S rRNA 测序和粪便代谢物分析,我们描述了这两个品系的非转基因(Ntg)和 SOD1G93A 突变小鼠的肠道微生物群组成和代谢物特征。我们的研究结果表明,转基因小鼠的转基因组成和功能存在品系特异性差异,尤其是在粪便样本中属于Erysipelotrichaceae的类群丰度以及短链和中链脂肪酸水平方面。SOD1突变会导致两个品系的基因组定植发生显著变化,C57Ola_G93A小鼠的变化与129 Sv小鼠相似,可能会影响疾病的发病机制。我们的发现强调了遗传背景对 ALS 小鼠模型中基因组的组成、代谢和免疫反应的重大影响。这些品系特异性差异可能会导致疾病易感性和进展率的不同。进一步阐明这些相互作用的内在机制可为了解 ALS 发病机制和潜在治疗靶点提供新的视角。
{"title":"Host genetics and gut microbiota influence lipid metabolism and inflammation: potential implications for ALS pathophysiology in SOD1<sup>G93A</sup> mice.","authors":"Elena Niccolai, Leandro Di Gloria, Maria Chiara Trolese, Paola Fabbrizio, Simone Baldi, Giulia Nannini, Cassandra Margotta, Claudia Nastasi, Matteo Ramazzotti, Gianluca Bartolucci, Caterina Bendotti, Giovanni Nardo, Amedeo Amdei","doi":"10.1186/s40478-024-01877-x","DOIUrl":"10.1186/s40478-024-01877-x","url":null,"abstract":"<p><p>Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons, with genetic and environmental factors contributing to its complex pathogenesis. Dysregulated immune responses and altered energetic metabolism are key features, with emerging evidence implicating the gut microbiota (GM) in disease progression. We investigated the interplay among genetic background, GM composition, metabolism, and immune response in two distinct ALS mouse models: 129Sv_G93A and C57Ola_G93A, representing rapid and slow disease progression, respectively.Using 16 S rRNA sequencing and fecal metabolite analysis, we characterized the GM composition and metabolite profiles in non-transgenic (Ntg) and SOD1<sup>G93A</sup> mutant mice of both strains. Our results revealed strain-specific differences in GM composition and functions, particularly in the abundance of taxa belonging to Erysipelotrichaceae and the levels of short and medium-chain fatty acids in fecal samples. The SOD1 mutation induces significant shifts in GM colonization in both strains, with C57Ola_G93A mice showing changes resembling those in 129 Sv mice, potentially affecting disease pathogenesis. ALS symptom progression does not significantly alter microbiota composition, suggesting stability.Additionally, we assessed systemic immunity and inflammatory responses revealing strain-specific differences in immune cell populations and cytokine levels.Our findings underscore the substantial influence of genetic background on GM composition, metabolism, and immune response in ALS mouse models. These strain-specific variations may contribute to differences in disease susceptibility and progression rates. Further elucidating the mechanisms underlying these interactions could offer novel insights into ALS pathogenesis and potential therapeutic targets.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589422","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 : 2024-10-29DOI: 10.1186/s40478-024-01875-z
Michael Chang, Mohamed Sherief, Maria Ioannou, Viveka Chinnasamy, Lucy Chen, Michael Frost, Michelle Mattson-Hoss, Herb Sarnoff, David O Kamson, Matthias Holdhoff, Debraj Mukherjee, Chetan Bettegowda, Jordina Rincon-Torroella, Victoria Croog, Peng Huang, Fausto J Rodriguez, Calixto-Hope G Lucas, Karisa C Schreck
Background: NF1 inactivation is associated with sensitivity to MEK inhibitor targeted therapy in low-grade and some high-grade gliomas. NF1 loss may also be a harbinger of exploitable vulnerabilities in IDH-wildtype glioblastoma (GBM). Accurate and consistent detection of NF1 loss, however, is fraught given the large gene size, challenges with complete coverage and variant calling upon sequencing, and mechanisms of mRNA and protein regulation that result in early degradation in the absence of genomic alterations. Here, we seek to perform a composite analysis for NF1 loss accounting for genomic alterations and protein expression via immunohistochemistry. We also characterize the landscape of NF1 alterations in GBM.
Methods: We assembled a single-institution, retrospective cohort of 542 IDH-wildtype GBM with somatic next generation sequencing to investigate the frequency and nature of detected NF1 alterations. We selected 69 GBMs from which to build a tissue microarray (TMA) of 44 NF1-wildtype and 25 NF1-mutant cases. We performed NF1 immunohistochemistry using two different NF1 antibodies (NFC, Sigma-Aldrich; and iNF-07E, iNFixion Bioscience) and correlated results with clinical, genomic, and other immunohistochemical features.
Results: In our retrospective cohort, we identified 88 IDH-wildtype GBM with NF1 alterations (16%). NF1 alterations were mutually exclusive with EGFR and MDM2 alterations (p-adj < 0.001, 0.05, respectively), but co-occurred with PIK3R1 alterations (Log2(OR) = - 1.6, p-adj = 0.03). Of the 63 scorable sporadic GBMs in the TMA, 14 harbored NF1 inactivating alterations and of those, 12 (86%) demonstrated minimal NF1 immunoreactivity by NFC antibody, compared to 8 (57%) by iNF-07E antibody. Among the 42 scorable NF1-wildtype GBM in the TMA, NF1 immunostaining was minimal in 18 (43%) by NFC antibody compared to 4 (10%) by iNF-07E antibody, potentially reflecting false positives or differential protein regulation. Minimal immunoreactivity by NFC antibody was associated with decreased median overall survival (8.5 vs. 16.4 months, p = 0.011). Cox proportional hazards model correcting for prognostic variables in this subset revealed HR 3.23 (95% CI 1.29-8.06, p = 0.01) associated with decreased NF1 expression by IHC.
Conclusion: NF1 immunostaining may serve as a sensitive surrogate marker of NF1 genomic inactivation and a valuable extension to next-generation sequencing for defining NF1 status. Minimal NF1 immunoreactivity is a poor prognostic marker, even in IDH-wildtype glioblastoma without apparent NF1 genomic alterations, but the underlying molecular mechanism requires further investigation.
{"title":"NF1 expression profiling in IDH-wildtype glioblastoma: genomic associations and survival outcomes.","authors":"Michael Chang, Mohamed Sherief, Maria Ioannou, Viveka Chinnasamy, Lucy Chen, Michael Frost, Michelle Mattson-Hoss, Herb Sarnoff, David O Kamson, Matthias Holdhoff, Debraj Mukherjee, Chetan Bettegowda, Jordina Rincon-Torroella, Victoria Croog, Peng Huang, Fausto J Rodriguez, Calixto-Hope G Lucas, Karisa C Schreck","doi":"10.1186/s40478-024-01875-z","DOIUrl":"10.1186/s40478-024-01875-z","url":null,"abstract":"<p><strong>Background: </strong>NF1 inactivation is associated with sensitivity to MEK inhibitor targeted therapy in low-grade and some high-grade gliomas. NF1 loss may also be a harbinger of exploitable vulnerabilities in IDH-wildtype glioblastoma (GBM). Accurate and consistent detection of NF1 loss, however, is fraught given the large gene size, challenges with complete coverage and variant calling upon sequencing, and mechanisms of mRNA and protein regulation that result in early degradation in the absence of genomic alterations. Here, we seek to perform a composite analysis for NF1 loss accounting for genomic alterations and protein expression via immunohistochemistry. We also characterize the landscape of NF1 alterations in GBM.</p><p><strong>Methods: </strong>We assembled a single-institution, retrospective cohort of 542 IDH-wildtype GBM with somatic next generation sequencing to investigate the frequency and nature of detected NF1 alterations. We selected 69 GBMs from which to build a tissue microarray (TMA) of 44 NF1-wildtype and 25 NF1-mutant cases. We performed NF1 immunohistochemistry using two different NF1 antibodies (NFC, Sigma-Aldrich; and iNF-07E, iNFixion Bioscience) and correlated results with clinical, genomic, and other immunohistochemical features.</p><p><strong>Results: </strong>In our retrospective cohort, we identified 88 IDH-wildtype GBM with NF1 alterations (16%). NF1 alterations were mutually exclusive with EGFR and MDM2 alterations (p-adj < 0.001, 0.05, respectively), but co-occurred with PIK3R1 alterations (Log<sub>2</sub>(OR) = - 1.6, p-adj = 0.03). Of the 63 scorable sporadic GBMs in the TMA, 14 harbored NF1 inactivating alterations and of those, 12 (86%) demonstrated minimal NF1 immunoreactivity by NFC antibody, compared to 8 (57%) by iNF-07E antibody. Among the 42 scorable NF1-wildtype GBM in the TMA, NF1 immunostaining was minimal in 18 (43%) by NFC antibody compared to 4 (10%) by iNF-07E antibody, potentially reflecting false positives or differential protein regulation. Minimal immunoreactivity by NFC antibody was associated with decreased median overall survival (8.5 vs. 16.4 months, p = 0.011). Cox proportional hazards model correcting for prognostic variables in this subset revealed HR 3.23 (95% CI 1.29-8.06, p = 0.01) associated with decreased NF1 expression by IHC.</p><p><strong>Conclusion: </strong>NF1 immunostaining may serve as a sensitive surrogate marker of NF1 genomic inactivation and a valuable extension to next-generation sequencing for defining NF1 status. Minimal NF1 immunoreactivity is a poor prognostic marker, even in IDH-wildtype glioblastoma without apparent NF1 genomic alterations, but the underlying molecular mechanism requires further investigation.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542817","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 : 2024-10-28DOI: 10.1186/s40478-024-01878-w
Michio Inoue, Divya Jayaraman, Rocio Bengoechea, Ankan Bhadra, Casie A Genetti, Abdulrahman A Aldeeri, Betül Turan, Rafael Adrian Pacheco-Orozco, Almundher Al-Maawali, Nadia Al Hashmi, Ayşe Gül Zamani, Emine Göktaş, Sevgi Pekcan, Hanife Tuğçe Çağlar, Heather True, Alan H Beggs, Conrad C Weihl
Protein aggregate myopathies can result from pathogenic variants in genes encoding protein chaperones. DNAJB4 is a cochaperone belonging to the heat shock protein-40 (HSP40) family and plays a vital role in cellular proteostasis. Recessive loss-of-function variants in DNAJB4 cause myopathy with early respiratory failure and spinal rigidity, presenting from infancy to adulthood. This study investigated the broader clinical and genetic spectrum of DNAJB4 myopathy. In this study, we performed whole-exome sequencing on seven patients with early respiratory failure of unknown genetic etiology. We identified five distinct pathogenic variants in DNAJB4 in five unrelated families of diverse ethnic backgrounds: three loss-of-function variants (c.547 C > T, p.R183*; c.775 C > T, p.R259*; an exon 2 deletion) and two missense variants (c.105G > C, p.K35N; c.181 A > G, p.R61G). All patients were homozygous. Most affected individuals exhibited early respiratory failure, and patients from three families had rigid spine syndrome with axial weakness in proportion to appendicular weakness. Additional symptoms included dysphagia, ankle contractures, scoliosis, neck stiffness, and cardiac dysfunction. Notably, J-domain missense variants were associated with a more severe phenotype, including an earlier age of onset and a higher mortality rate, suggesting a strong genotype‒phenotype correlation. Consistent with a loss of function, the nonsense variants presented decreased stability. In contrast, the missense variants exhibited normal or increased stability but behaved as loss-of-function variants in yeast complementation and TDP-43 disaggregation assays. Our findings suggest that DNAJB4 is an emerging cause of myopathy with rigid spine syndrome of variable age of onset and severity. This diagnosis should be considered in individuals presenting with suggestive symptoms, particularly if they exhibit neck stiffness during infancy or experience respiratory failure in adults without significant limb muscle weakness. Missense variants in the J domain may predict a more severe phenotype.
编码蛋白伴侣的基因中的致病变异可导致蛋白聚集性肌病。DNAJB4 是一种属于热休克蛋白-40(HSP40)家族的伴侣蛋白,在细胞蛋白稳态中发挥着重要作用。DNAJB4 的隐性功能缺失变体会导致肌病,并伴有早期呼吸衰竭和脊柱僵硬,从婴儿期一直持续到成年期。本研究调查了DNAJB4肌病更广泛的临床和遗传谱。在这项研究中,我们对七名遗传病因不明的早期呼吸衰竭患者进行了全外显子组测序。我们在五个不同种族背景的无亲属关系家庭中发现了 DNAJB4 的五个不同致病变异:三个功能缺失变异(c.547 C > T,p.R183*;c.775 C > T,p.R259*;一个外显子 2 缺失)和两个错义变异(c.105G > C,p.K35N;c.181 A > G,p.R61G)。所有患者均为同型变异。大多数患者表现出早期呼吸衰竭,三个家族的患者患有脊柱僵硬综合征,轴向无力与阑尾无力成正比。其他症状包括吞咽困难、踝关节挛缩、脊柱侧弯、颈部僵硬和心脏功能障碍。值得注意的是,J-domain 错义变异与更严重的表型有关,包括更早的发病年龄和更高的死亡率,这表明基因型与表型之间存在很强的相关性。与功能缺失相一致的是,无义变体的稳定性降低。相反,错义变体表现出正常或更高的稳定性,但在酵母互补和TDP-43分解试验中表现为功能缺失变体。我们的研究结果表明,DNAJB4 是导致发病年龄和严重程度不一的脊柱僵直综合征肌病的一个新病因。如果患者出现提示性症状,尤其是在婴儿期表现出颈部僵硬或在成年后出现呼吸衰竭而无明显四肢肌无力时,应考虑这一诊断。J 结构域的错义变异可能预示着更严重的表型。
{"title":"Genotype‒phenotype correlation in recessive DNAJB4 myopathy.","authors":"Michio Inoue, Divya Jayaraman, Rocio Bengoechea, Ankan Bhadra, Casie A Genetti, Abdulrahman A Aldeeri, Betül Turan, Rafael Adrian Pacheco-Orozco, Almundher Al-Maawali, Nadia Al Hashmi, Ayşe Gül Zamani, Emine Göktaş, Sevgi Pekcan, Hanife Tuğçe Çağlar, Heather True, Alan H Beggs, Conrad C Weihl","doi":"10.1186/s40478-024-01878-w","DOIUrl":"10.1186/s40478-024-01878-w","url":null,"abstract":"<p><p>Protein aggregate myopathies can result from pathogenic variants in genes encoding protein chaperones. DNAJB4 is a cochaperone belonging to the heat shock protein-40 (HSP40) family and plays a vital role in cellular proteostasis. Recessive loss-of-function variants in DNAJB4 cause myopathy with early respiratory failure and spinal rigidity, presenting from infancy to adulthood. This study investigated the broader clinical and genetic spectrum of DNAJB4 myopathy. In this study, we performed whole-exome sequencing on seven patients with early respiratory failure of unknown genetic etiology. We identified five distinct pathogenic variants in DNAJB4 in five unrelated families of diverse ethnic backgrounds: three loss-of-function variants (c.547 C > T, p.R183*; c.775 C > T, p.R259*; an exon 2 deletion) and two missense variants (c.105G > C, p.K35N; c.181 A > G, p.R61G). All patients were homozygous. Most affected individuals exhibited early respiratory failure, and patients from three families had rigid spine syndrome with axial weakness in proportion to appendicular weakness. Additional symptoms included dysphagia, ankle contractures, scoliosis, neck stiffness, and cardiac dysfunction. Notably, J-domain missense variants were associated with a more severe phenotype, including an earlier age of onset and a higher mortality rate, suggesting a strong genotype‒phenotype correlation. Consistent with a loss of function, the nonsense variants presented decreased stability. In contrast, the missense variants exhibited normal or increased stability but behaved as loss-of-function variants in yeast complementation and TDP-43 disaggregation assays. Our findings suggest that DNAJB4 is an emerging cause of myopathy with rigid spine syndrome of variable age of onset and severity. This diagnosis should be considered in individuals presenting with suggestive symptoms, particularly if they exhibit neck stiffness during infancy or experience respiratory failure in adults without significant limb muscle weakness. Missense variants in the J domain may predict a more severe phenotype.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520631","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 : 2024-10-28DOI: 10.1186/s40478-024-01874-0
Steven C Pike, John K Wiencke, Ze Zhang, Annette M Molinaro, Helen M Hansen, Devin C Koestler, Brock C Christensen, Karl T Kelsey, Lucas A Salas
A scalable platform for cell typing in the glioma microenvironment can improve tumor subtyping and immune landscape detection as successful immunotherapy strategies continue to be sought and evaluated. DNA methylation (DNAm) biomarkers for molecular classification of tumor subtypes have been developed for clinical use. However, tools that predict the cellular landscape of the tumor are not well-defined or readily available. We developed the Glioma Immune Microenvironment Composition Calculator (GIMiCC), an approach for deconvolution of cell types in gliomas using DNAm data. Using data from 17 isolated cell types, we describe the derivation of the deconvolution libraries in the biological context of selected genomic regions and validate deconvolution results using independent datasets. We utilize GIMiCC to illustrate that DNAm-based estimates of immune composition are clinically relevant and scalable for potential clinical implementation. In addition, we utilize GIMiCC to identify composition-independent DNAm alterations that are associated with high immune infiltration. Our future work aims to optimize GIMiCC and advance the clinical evaluation of glioma.
{"title":"Glioma immune microenvironment composition calculator (GIMiCC): a method of estimating the proportions of eighteen cell types from DNA methylation microarray data.","authors":"Steven C Pike, John K Wiencke, Ze Zhang, Annette M Molinaro, Helen M Hansen, Devin C Koestler, Brock C Christensen, Karl T Kelsey, Lucas A Salas","doi":"10.1186/s40478-024-01874-0","DOIUrl":"10.1186/s40478-024-01874-0","url":null,"abstract":"<p><p>A scalable platform for cell typing in the glioma microenvironment can improve tumor subtyping and immune landscape detection as successful immunotherapy strategies continue to be sought and evaluated. DNA methylation (DNAm) biomarkers for molecular classification of tumor subtypes have been developed for clinical use. However, tools that predict the cellular landscape of the tumor are not well-defined or readily available. We developed the Glioma Immune Microenvironment Composition Calculator (GIMiCC), an approach for deconvolution of cell types in gliomas using DNAm data. Using data from 17 isolated cell types, we describe the derivation of the deconvolution libraries in the biological context of selected genomic regions and validate deconvolution results using independent datasets. We utilize GIMiCC to illustrate that DNAm-based estimates of immune composition are clinically relevant and scalable for potential clinical implementation. In addition, we utilize GIMiCC to identify composition-independent DNAm alterations that are associated with high immune infiltration. Our future work aims to optimize GIMiCC and advance the clinical evaluation of glioma.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520632","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}
Mutations in the isocitrate dehydrogenase (IDH) gene are recognized as the key drivers in the oncogenesis of astrocytoma and oligodendroglioma. However, the significance of IDH mutation in tumor maintenance and malignant transformation has not been elucidated. We encountered a unique case of IDH-mutant astrocytoma that, upon malignant transformation, presented two distinct intratumoral components: one IDH-wildtype and one IDH-mutant. The IDH-wild-type component exhibited histological findings similar to those of small cell-type glioblastoma with a higher Ki-67 index than the IDH-mutant component. Despite their genetic divergence, both components exhibited similar comprehensive methylation profiles within the CpG island and were classified into methylation class of "Astrocytoma, IDH-mutant; High Grade" by the German Cancer Center (DKFZ) classifier v11.4. Phylogenetic analysis demonstrated that the IDH-wildtype component emerged as a subclonal component of the primary tumor. Detailed molecular analyses revealed that the loss of the IDH mutation was induced by the hemizygous loss of the entire arm of chromosome 2, on which IDH1 gene is located. Notably, the IDH-wild-type subclones uniquely acquired CDKN2A/B homozygous deletion and PDGFRA amplification, which is a marker of the aggressive phenotype of astrocytoma, IDH-mutant. Because these genetic abnormalities can drive oncogenic pathways, such as the PI3K/AKT/mTOR and RB signaling pathway, IDH-mutant gliomas that acquired these mutations were no longer dependent on the initial driver mutation, the IDH mutation. Molecular analysis of this unique case provides insight that in a subset of astrocytoma, IDH-mutant that acquired these genetic abnormalities, IDH mutation may not play a pivotal role in tumor growth and acquisition of these genetic abnormalities may contribute to the acquisition of resistance to IDH inhibitors.
{"title":"Dual phenotypes in recurrent astrocytoma, IDH-mutant; coexistence of IDH-mutant and IDH-wildtype components: a case report with genetic and epigenetic analysis.","authors":"Junya Yamaguchi, Fumiharu Ohka, Masafumi Seki, Kazuya Motomura, Shoichi Deguchi, Yoshiki Shiba, Yuka Okumura, Yuji Kibe, Hiroki Shimizu, Sachi Maeda, Yuhei Takido, Ryo Yamamoto, Akihiro Nakamura, Kennosuke Karube, Ryuta Saito","doi":"10.1186/s40478-024-01879-9","DOIUrl":"10.1186/s40478-024-01879-9","url":null,"abstract":"<p><p>Mutations in the isocitrate dehydrogenase (IDH) gene are recognized as the key drivers in the oncogenesis of astrocytoma and oligodendroglioma. However, the significance of IDH mutation in tumor maintenance and malignant transformation has not been elucidated. We encountered a unique case of IDH-mutant astrocytoma that, upon malignant transformation, presented two distinct intratumoral components: one IDH-wildtype and one IDH-mutant. The IDH-wild-type component exhibited histological findings similar to those of small cell-type glioblastoma with a higher Ki-67 index than the IDH-mutant component. Despite their genetic divergence, both components exhibited similar comprehensive methylation profiles within the CpG island and were classified into methylation class of \"Astrocytoma, IDH-mutant; High Grade\" by the German Cancer Center (DKFZ) classifier v11.4. Phylogenetic analysis demonstrated that the IDH-wildtype component emerged as a subclonal component of the primary tumor. Detailed molecular analyses revealed that the loss of the IDH mutation was induced by the hemizygous loss of the entire arm of chromosome 2, on which IDH1 gene is located. Notably, the IDH-wild-type subclones uniquely acquired CDKN2A/B homozygous deletion and PDGFRA amplification, which is a marker of the aggressive phenotype of astrocytoma, IDH-mutant. Because these genetic abnormalities can drive oncogenic pathways, such as the PI3K/AKT/mTOR and RB signaling pathway, IDH-mutant gliomas that acquired these mutations were no longer dependent on the initial driver mutation, the IDH mutation. Molecular analysis of this unique case provides insight that in a subset of astrocytoma, IDH-mutant that acquired these genetic abnormalities, IDH mutation may not play a pivotal role in tumor growth and acquisition of these genetic abnormalities may contribute to the acquisition of resistance to IDH inhibitors.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11515116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492582","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 : 2024-10-24DOI: 10.1186/s40478-024-01787-y
Claudio D'Incal, Anke Van Dijck, Joe Ibrahim, Kevin De Man, Lina Bastini, Anthony Konings, Ellen Elinck, Claudia Theys, Illana Gozes, Zlatko Marusic, Mirna Anicic, Jurica Vukovic, Nathalie Van der Aa, Ligia Mateiu, Wim Vanden Berghe, R Frank Kooy
{"title":"Correction to: ADNP dysregulates methylation and mitochondrial gene expression in the cerebellum of a Helsmoortel-Van Der Aa syndrome autopsy case.","authors":"Claudio D'Incal, Anke Van Dijck, Joe Ibrahim, Kevin De Man, Lina Bastini, Anthony Konings, Ellen Elinck, Claudia Theys, Illana Gozes, Zlatko Marusic, Mirna Anicic, Jurica Vukovic, Nathalie Van der Aa, Ligia Mateiu, Wim Vanden Berghe, R Frank Kooy","doi":"10.1186/s40478-024-01787-y","DOIUrl":"https://doi.org/10.1186/s40478-024-01787-y","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492581","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 : 2024-10-22DOI: 10.1186/s40478-024-01873-1
Zerui Wang, Tricia Gilliland, Hyun Jo Kim, Maria Gerasimenko, Kailey Sajewski, Manuel V Camacho, Gurkan Bebek, Shu G Chen, Steven A Gunzler, Qingzhong Kong
Seeding activities of disease-associated α-synuclein aggregates (αSynD), a hallmark of Parkinson's disease (PD), are detectable by seed amplification assay (αSyn-SAA) and being developed as a diagnostic biomarker for PD. Sensitive and accurate αSyn-SAA for blood or saliva would greatly facilitate PD diagnosis. This prospective diagnostic study conducted αSyn-SAA analyses on serum and saliva samples collected from patients clinically diagnosed with PD or healthy controls (HC). 124 subjects (82 PD, 42 HC) donated blood and had extensive clinical assessments, of whom 74 subjects (48 PD, 26 HC) also donated saliva at the same visits. An additional 57 subjects (35 PD, 22 HC) donated saliva and had more limited clinical assessments. The mean ages were 69.21, 66.55, 69.58, and 64.71 years for PD serum donors, HC serum donors, PD saliva donors, and HC saliva donors, respectively. αSynD seeding activities in either sample type alone or both sample types together were evaluated for PD diagnosis. Serum αSyn-SAA data from 124 subjects showed 80.49% sensitivity, 90.48% specificity, and 0.9006 accuracy (AUC of ROC); saliva αSyn-SAA data from 131 subjects attained 74.70% sensitivity, 97.92% specificity, and 0.8966 accuracy. Remarkably, the combined serum and saliva αSyn-SAA from 74 subjects with both sample types achieved better diagnostic performance: 95.83% sensitivity, 96.15% specificity, and 0.98 accuracy. In addition, serum αSynD seeding activities correlated inversely with Montreal Cognitive Assessment in males and positively with Hamilton Depression Rating Scale in females and in the < 70 age group, whereas saliva αSynD seeding activities correlated inversely with age at diagnosis in males and in the < 70 age group. Our data indicate that serum and saliva αSyn-SAA together can achieve high diagnostic accuracy for PD comparable to that of CSF αSyn-SAA, suggesting their potential utility for highly sensitive, accurate, and minimally invasive diagnosis of PD in routine clinical practice and clinical studies.
{"title":"A minimally invasive biomarker for sensitive and accurate diagnosis of Parkinson's disease.","authors":"Zerui Wang, Tricia Gilliland, Hyun Jo Kim, Maria Gerasimenko, Kailey Sajewski, Manuel V Camacho, Gurkan Bebek, Shu G Chen, Steven A Gunzler, Qingzhong Kong","doi":"10.1186/s40478-024-01873-1","DOIUrl":"10.1186/s40478-024-01873-1","url":null,"abstract":"<p><p>Seeding activities of disease-associated α-synuclein aggregates (αSyn<sup>D</sup>), a hallmark of Parkinson's disease (PD), are detectable by seed amplification assay (αSyn-SAA) and being developed as a diagnostic biomarker for PD. Sensitive and accurate αSyn-SAA for blood or saliva would greatly facilitate PD diagnosis. This prospective diagnostic study conducted αSyn-SAA analyses on serum and saliva samples collected from patients clinically diagnosed with PD or healthy controls (HC). 124 subjects (82 PD, 42 HC) donated blood and had extensive clinical assessments, of whom 74 subjects (48 PD, 26 HC) also donated saliva at the same visits. An additional 57 subjects (35 PD, 22 HC) donated saliva and had more limited clinical assessments. The mean ages were 69.21, 66.55, 69.58, and 64.71 years for PD serum donors, HC serum donors, PD saliva donors, and HC saliva donors, respectively. αSyn<sup>D</sup> seeding activities in either sample type alone or both sample types together were evaluated for PD diagnosis. Serum αSyn-SAA data from 124 subjects showed 80.49% sensitivity, 90.48% specificity, and 0.9006 accuracy (AUC of ROC); saliva αSyn-SAA data from 131 subjects attained 74.70% sensitivity, 97.92% specificity, and 0.8966 accuracy. Remarkably, the combined serum and saliva αSyn-SAA from 74 subjects with both sample types achieved better diagnostic performance: 95.83% sensitivity, 96.15% specificity, and 0.98 accuracy. In addition, serum αSyn<sup>D</sup> seeding activities correlated inversely with Montreal Cognitive Assessment in males and positively with Hamilton Depression Rating Scale in females and in the < 70 age group, whereas saliva αSyn<sup>D</sup> seeding activities correlated inversely with age at diagnosis in males and in the < 70 age group. Our data indicate that serum and saliva αSyn-SAA together can achieve high diagnostic accuracy for PD comparable to that of CSF αSyn-SAA, suggesting their potential utility for highly sensitive, accurate, and minimally invasive diagnosis of PD in routine clinical practice and clinical studies.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492580","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 : 2024-10-21DOI: 10.1186/s40478-024-01871-3
Sunniva M K Bøstrand, Luise A Seeker, Nadine Bestard-Cuche, Nina-Lydia Kazakou, Sarah Jäkel, Boyd Kenkhuis, Neil C Henderson, Susanne T de Bot, Willeke M C van Roon-Mom, Josef Priller, Anna Williams
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease with a fatal outcome. There is accumulating evidence of a prominent role of glia in the pathology of HD, and we investigated this by conducting single nuclear RNA sequencing (snRNAseq) of human post mortem brain in four differentially affected regions; caudate nucleus, frontal cortex, hippocampus and cerebellum. Across 127,205 nuclei from donors with HD and age/sex matched controls, we found heterogeneity of glia which is altered in HD. We describe prominent changes in the abundance of certain subtypes of astrocytes, microglia, oligodendrocyte precursor cells and oligodendrocytes between HD and control samples, and these differences are widespread across brain regions. Furthermore, we highlight possible mechanisms that characterise the glial contribution to HD pathology including depletion of myelinating oligodendrocytes, an oligodendrocyte-specific upregulation of the calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1 A (PDE1A) and an upregulation of molecular chaperones as a cross-glial signature and a potential adaptive response to the accumulation of mutant huntingtin (mHTT). Our results support the hypothesis that glia have an important role in the pathology of HD, and show that all types of glia are affected in the disease.
亨廷顿氏病(Huntington's disease,HD)是一种常染色体显性神经退行性疾病,具有致命性。越来越多的证据表明,神经胶质细胞在 HD 的病理过程中起着重要作用。我们通过对人类死后大脑的四个不同受影响区域(尾状核、额叶皮层、海马和小脑)进行单核 RNA 测序(snRNAseq)进行了研究。在来自 HD 供体和年龄/性别匹配的对照组的 127,205 个细胞核中,我们发现神经胶质细胞的异质性在 HD 中发生了改变。我们描述了 HD 和对照组样本中某些亚型星形胶质细胞、小胶质细胞、少突胶质细胞前体细胞和少突胶质细胞丰度的显著变化,这些差异广泛存在于各个脑区。此外,我们还强调了神经胶质对 HD 病理学的可能作用机制,包括髓鞘化少突胶质细胞的耗竭、少突胶质细胞特异性上调钙调蛋白依赖性 3',5'-环核苷酸磷酸二酯酶 1 A (PDE1A)、作为跨神经胶质特征的分子伴侣上调以及对突变亨廷汀(mHTT)累积的潜在适应性反应。我们的研究结果支持神经胶质细胞在HD病理学中扮演重要角色的假设,并表明所有类型的神经胶质细胞都会受到该疾病的影响。
{"title":"Mapping the glial transcriptome in Huntington's disease using snRNAseq: selective disruption of glial signatures across brain regions.","authors":"Sunniva M K Bøstrand, Luise A Seeker, Nadine Bestard-Cuche, Nina-Lydia Kazakou, Sarah Jäkel, Boyd Kenkhuis, Neil C Henderson, Susanne T de Bot, Willeke M C van Roon-Mom, Josef Priller, Anna Williams","doi":"10.1186/s40478-024-01871-3","DOIUrl":"10.1186/s40478-024-01871-3","url":null,"abstract":"<p><p>Huntington's disease (HD) is an autosomal dominant neurodegenerative disease with a fatal outcome. There is accumulating evidence of a prominent role of glia in the pathology of HD, and we investigated this by conducting single nuclear RNA sequencing (snRNAseq) of human post mortem brain in four differentially affected regions; caudate nucleus, frontal cortex, hippocampus and cerebellum. Across 127,205 nuclei from donors with HD and age/sex matched controls, we found heterogeneity of glia which is altered in HD. We describe prominent changes in the abundance of certain subtypes of astrocytes, microglia, oligodendrocyte precursor cells and oligodendrocytes between HD and control samples, and these differences are widespread across brain regions. Furthermore, we highlight possible mechanisms that characterise the glial contribution to HD pathology including depletion of myelinating oligodendrocytes, an oligodendrocyte-specific upregulation of the calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1 A (PDE1A) and an upregulation of molecular chaperones as a cross-glial signature and a potential adaptive response to the accumulation of mutant huntingtin (mHTT). Our results support the hypothesis that glia have an important role in the pathology of HD, and show that all types of glia are affected in the disease.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11492505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455413","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 : 2024-10-21DOI: 10.1186/s40478-024-01876-y
Florian Perrin, Lauren C Anderson, Shane P C Mitchell, Priyanka Sinha, Yuliia Turchyna, Masato Maesako, Mei C Q Houser, Can Zhang, Steven L Wagner, Rudolph E Tanzi, Oksana Berezovska
The recently discovered interaction between presenilin 1 (PS1), a subunit of γ-secretase involved in amyloid-β (Aβ) peptide production, and GLT-1, the major brain glutamate transporter (EAAT2 in the human), may link two pathological aspects of Alzheimer's disease: abnormal Aβ occurrence and neuronal network hyperactivity. In the current study, we employed a FRET-based fluorescence lifetime imaging microscopy (FLIM) to characterize the PS1/GLT-1 interaction in brain tissue from sporadic AD (sAD) patients. sAD brains showed significantly less PS1/GLT-1 interaction than those with frontotemporal lobar degeneration or non-demented controls. Familial AD (fAD) PS1 mutations, inducing a "closed" PS1 conformation similar to that in sAD brain, and gamma-secretase modulators (GSMs), inducing a "relaxed" conformation, respectively reduced and increased the interaction. Furthermore, PS1 influences GLT-1 cell surface expression and homomultimer formation, acting as a chaperone but not affecting GLT-1 stability. The diminished PS1/GLT-1 interaction suggests that these functions may not work properly in AD.
{"title":"PS1/gamma-secretase acts as rogue chaperone of glutamate transporter EAAT2/GLT-1 in Alzheimer's disease.","authors":"Florian Perrin, Lauren C Anderson, Shane P C Mitchell, Priyanka Sinha, Yuliia Turchyna, Masato Maesako, Mei C Q Houser, Can Zhang, Steven L Wagner, Rudolph E Tanzi, Oksana Berezovska","doi":"10.1186/s40478-024-01876-y","DOIUrl":"10.1186/s40478-024-01876-y","url":null,"abstract":"<p><p>The recently discovered interaction between presenilin 1 (PS1), a subunit of γ-secretase involved in amyloid-β (Aβ) peptide production, and GLT-1, the major brain glutamate transporter (EAAT2 in the human), may link two pathological aspects of Alzheimer's disease: abnormal Aβ occurrence and neuronal network hyperactivity. In the current study, we employed a FRET-based fluorescence lifetime imaging microscopy (FLIM) to characterize the PS1/GLT-1 interaction in brain tissue from sporadic AD (sAD) patients. sAD brains showed significantly less PS1/GLT-1 interaction than those with frontotemporal lobar degeneration or non-demented controls. Familial AD (fAD) PS1 mutations, inducing a \"closed\" PS1 conformation similar to that in sAD brain, and gamma-secretase modulators (GSMs), inducing a \"relaxed\" conformation, respectively reduced and increased the interaction. Furthermore, PS1 influences GLT-1 cell surface expression and homomultimer formation, acting as a chaperone but not affecting GLT-1 stability. The diminished PS1/GLT-1 interaction suggests that these functions may not work properly in AD.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11492509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455414","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}