Pub Date : 2024-06-01Epub Date: 2024-06-12DOI: 10.1098/rsob.230448
Danuta Mizgalska, Arturo Rodríguez-Banqueri, Florian Veillard, Mirosław Książęk, Theodoros Goulas, Tibisay Guevara, Ulrich Eckhard, Jan Potempa, F Xavier Gomis-Rüth
Gram-negative bacteria from the Bacteroidota phylum possess a type-IX secretion system (T9SS) for protein secretion, which requires cargoes to have a C-terminal domain (CTD). Structurally analysed CTDs are from Porphyromonas gingivalis proteins RgpB, HBP35, PorU and PorZ, which share a compact immunoglobulin-like antiparallel 3+4 β-sandwich (β1-β7). This architecture is essential as a P. gingivalis strain with a single-point mutant of RgpB disrupting the interaction of the CTD with its preceding domain prevented secretion of the protein. Next, we identified the C-terminus ('motif C-t.') and the loop connecting strands β3 and β4 ('motif Lβ3β4') as conserved. We generated two strains with insertion and replacement mutants of PorU, as well as three strains with ablation and point mutants of RgpB, which revealed both motifs to be relevant for T9SS function. Furthermore, we determined the crystal structure of the CTD of mirolase, a cargo of the Tannerella forsythia T9SS, which shares the same general topology as in Porphyromonas CTDs. However, motif Lβ3β4 was not conserved. Consistently, P. gingivalis could not properly secrete a chimaeric protein with the CTD of peptidylarginine deiminase replaced with this foreign CTD. Thus, the incompatibility of the CTDs between these species prevents potential interference between their T9SSs.
{"title":"Structural and functional insights into the C-terminal signal domain of the Bacteroidetes type-IX secretion system.","authors":"Danuta Mizgalska, Arturo Rodríguez-Banqueri, Florian Veillard, Mirosław Książęk, Theodoros Goulas, Tibisay Guevara, Ulrich Eckhard, Jan Potempa, F Xavier Gomis-Rüth","doi":"10.1098/rsob.230448","DOIUrl":"10.1098/rsob.230448","url":null,"abstract":"<p><p>Gram-negative bacteria from the Bacteroidota phylum possess a type-IX secretion system (T9SS) for protein secretion, which requires cargoes to have a C-terminal domain (CTD). Structurally analysed CTDs are from <i>Porphyromonas gingivalis</i> proteins RgpB, HBP35, PorU and PorZ, which share a compact immunoglobulin-like antiparallel 3+4 β-sandwich (β1-β7). This architecture is essential as a <i>P. gingivalis</i> strain with a single-point mutant of RgpB disrupting the interaction of the CTD with its preceding domain prevented secretion of the protein. Next, we identified the C-terminus ('motif C-t.') and the loop connecting strands β3 and β4 ('motif Lβ3β4') as conserved. We generated two strains with insertion and replacement mutants of PorU, as well as three strains with ablation and point mutants of RgpB, which revealed both motifs to be relevant for T9SS function. Furthermore, we determined the crystal structure of the CTD of mirolase, a cargo of the <i>Tannerella forsythia</i> T9SS<i>,</i> which shares the same general topology as in <i>Porphyromonas</i> CTDs. However, motif Lβ3β4 was not conserved. Consistently, <i>P. gingivalis</i> could not properly secrete a chimaeric protein with the CTD of peptidylarginine deiminase replaced with this foreign CTD. Thus, the incompatibility of the CTDs between these species prevents potential interference between their T9SSs.</p>","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hypertrophic cardiomyopathy (HCM) is a monogenic cardiac disorder commonly induced by sarcomere gene mutations. However, the mechanism for HCM is not well defined. Here, we generated transgenic MYH7 R453C and MYH6 R453C piglets and found both developed typical cardiac hypertrophy. Unexpectedly, we found serious fibrosis and cardiomyocyte loss in the ventricular of MYH7 R453C, not MYH6 R453C piglets, similar to HCM patients. Then, RNA-seq analysis and western blotting identified the activation of ERK1/2 and PI3K-Akt pathways in MYH7 R453C. Moreover, we observed an increased expression of fetal genes and an excess of reactive oxygen species (ROS) in MYH7 R453C piglet models, which was produced by Nox4 and subsequently induced inflammatory response. Additionally, the phosphorylation levels of Smad2/3, ERK1/2 and NF-kB p65 proteins were elevated in cardiomyocytes with the MYH7 R453C mutation. Furthermore, epigallocatechin gallate, a natural bioactive compound, could be used as a drug to reduce cell death by adjusting significant downregulation of the protein expression of Bax and upregulated Bcl-2 levels in the H9C2 models with MYH7 R453C mutation. In conclusion, our study illustrated that TGF-β/Smad2/3, ERK1/2 and Nox4/ROS pathways have synergistic effects on cardiac remodelling and inflammation in MYH7 R453C mutation.
{"title":"MYH7 R453C induced cardiac remodelling via activating TGF-β/Smad2/3, ERK1/2 and Nox4/ROS/NF-κB signalling pathways.","authors":"Lingyu Wang, Linquan Li, Dazhong Zhao, Hongming Yuan, Huanyu Zhang, Jiahuan Chen, Daxin Pang, Yi Lu, Hongsheng Ouyang","doi":"10.1098/rsob.230427","DOIUrl":"10.1098/rsob.230427","url":null,"abstract":"<p><p>Hypertrophic cardiomyopathy (HCM) is a monogenic cardiac disorder commonly induced by sarcomere gene mutations. However, the mechanism for HCM is not well defined. Here, we generated transgenic MYH7 R453C and MYH6 R453C piglets and found both developed typical cardiac hypertrophy. Unexpectedly, we found serious fibrosis and cardiomyocyte loss in the ventricular of MYH7 R453C, not MYH6 R453C piglets, similar to HCM patients. Then, RNA-seq analysis and western blotting identified the activation of ERK1/2 and PI3K-Akt pathways in MYH7 R453C. Moreover, we observed an increased expression of fetal genes and an excess of reactive oxygen species (ROS) in MYH7 R453C piglet models, which was produced by Nox4 and subsequently induced inflammatory response. Additionally, the phosphorylation levels of Smad2/3, ERK1/2 and NF-kB p65 proteins were elevated in cardiomyocytes with the MYH7 R453C mutation. Furthermore, epigallocatechin gallate, a natural bioactive compound, could be used as a drug to reduce cell death by adjusting significant downregulation of the protein expression of Bax and upregulated Bcl-2 levels in the H9C2 models with MYH7 R453C mutation. In conclusion, our study illustrated that TGF-β/Smad2/3, ERK1/2 and Nox4/ROS pathways have synergistic effects on cardiac remodelling and inflammation in MYH7 R453C mutation.</p>","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-06-05DOI: 10.1098/rsob.230418
Luke McAlary, Jeremy R Nan, Clay Shyu, Mine Sher, Steven S Plotkin, Neil R Cashman
Mutations in the protein superoxide dismutase-1 (SOD1) promote its misfolding and aggregation, ultimately causing familial forms of the debilitating neurodegenerative disease amyotrophic lateral sclerosis (ALS). Currently, over 220 (mostly missense) ALS-causing mutations in the SOD1 protein have been identified, indicating that common structural features are responsible for aggregation and toxicity. Using in silico tools, we predicted amyloidogenic regions in the ALS-associated SOD1-G85R mutant, finding seven regions throughout the structure. Introduction of proline residues into β-strands II (I18P) or III (I35P) reduced the aggregation propensity and toxicity of SOD1-G85R in cells, significantly more so than proline mutations in other amyloidogenic regions. The I18P and I35P mutations also reduced the capability of SOD1-G85R to template onto previously formed non-proline mutant SOD1 aggregates as measured by fluorescence recovery after photobleaching. Finally, we found that, while the I18P and I35P mutants are less structurally stable than SOD1-G85R, the proline mutants are less aggregation-prone during proteasome inhibition, and less toxic to cells overall. Our research highlights the importance of a previously underappreciated SOD1 amyloidogenic region in β-strand II (15QGIINF20) to the aggregation and toxicity of SOD1 in ALS mutants, and suggests that β-strands II and III may be good targets for the development of SOD1-associated ALS therapies.
超氧化物歧化酶-1(SOD1)蛋白的突变会促进其错误折叠和聚集,最终导致家族性神经退行性疾病肌萎缩性脊髓侧索硬化症(ALS)。目前,在 SOD1 蛋白中发现了 220 多种导致 ALS 的突变(大部分是错义突变),这表明共同的结构特征是导致聚集和毒性的原因。我们利用硅学工具预测了与 ALS 相关的 SOD1-G85R 突变体中的淀粉样蛋白生成区域,发现整个结构中有七个区域。在β链II(I18P)或III(I35P)中引入脯氨酸残基可降低SOD1-G85R在细胞中的聚集倾向和毒性,其效果明显优于其他淀粉样变性区域的脯氨酸突变。I18P 和 I35P 突变还降低了 SOD1-G85R 在先前形成的非脯氨酸突变 SOD1 聚集体上的模板能力,这是用光漂白后的荧光恢复来测量的。最后,我们发现,虽然 I18P 和 I35P 突变体的结构稳定性不如 SOD1-G85R,但脯氨酸突变体在蛋白酶体抑制过程中不易发生聚集,而且总体上对细胞的毒性较低。我们的研究强调了以前未被重视的 SOD1 β 链 II(15QGIINF20)淀粉样蛋白生成区对 SOD1 在 ALS 突变体中的聚集和毒性的重要性,并表明 β 链 II 和 III 可能是开发 SOD1 相关 ALS 疗法的良好靶点。
{"title":"Amyloidogenic regions in beta-strands II and III modulate the aggregation and toxicity of SOD1 in living cells.","authors":"Luke McAlary, Jeremy R Nan, Clay Shyu, Mine Sher, Steven S Plotkin, Neil R Cashman","doi":"10.1098/rsob.230418","DOIUrl":"10.1098/rsob.230418","url":null,"abstract":"<p><p>Mutations in the protein superoxide dismutase-1 (SOD1) promote its misfolding and aggregation, ultimately causing familial forms of the debilitating neurodegenerative disease amyotrophic lateral sclerosis (ALS). Currently, over 220 (mostly missense) ALS-causing mutations in the SOD1 protein have been identified, indicating that common structural features are responsible for aggregation and toxicity. Using <i>in silico</i> tools, we predicted amyloidogenic regions in the ALS-associated SOD1-G85R mutant, finding seven regions throughout the structure. Introduction of proline residues into β-strands II (I18P) or III (I35P) reduced the aggregation propensity and toxicity of SOD1-G85R in cells, significantly more so than proline mutations in other amyloidogenic regions. The I18P and I35P mutations also reduced the capability of SOD1-G85R to template onto previously formed non-proline mutant SOD1 aggregates as measured by fluorescence recovery after photobleaching. Finally, we found that, while the I18P and I35P mutants are less structurally stable than SOD1-G85R, the proline mutants are less aggregation-prone during proteasome inhibition, and less toxic to cells overall. Our research highlights the importance of a previously underappreciated SOD1 amyloidogenic region in β-strand II (<sup>15</sup>QGIINF<sup>20</sup>) to the aggregation and toxicity of SOD1 in ALS mutants, and suggests that β-strands II and III may be good targets for the development of SOD1-associated ALS therapies.</p>","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-06-12DOI: 10.1098/rsob.230449
Brian Yao, Chloe Hsu, Gal Goldner, Yael Michaeli, Yuval Ebenstein, Jennifer Listgarten
Nanopore sequencing platforms combined with supervised machine learning (ML) have been effective at detecting base modifications in DNA such as 5-methylcytosine (5mC) and N6-methyladenine (6mA). These ML-based nanopore callers have typically been trained on data that span all modifications on all possible DNA [Formula: see text]-mer backgrounds-a complete training dataset. However, as nanopore technology is pushed to more and more epigenetic modifications, such complete training data will not be feasible to obtain. Nanopore calling has historically been performed with hidden Markov models (HMMs) that cannot make successful calls for [Formula: see text]-mer contexts not seen during training because of their independent emission distributions. However, deep neural networks (DNNs), which share parameters across contexts, are increasingly being used as callers, often outperforming their HMM cousins. It stands to reason that a DNN approach should be able to better generalize to unseen [Formula: see text]-mer contexts. Indeed, herein we demonstrate that a common DNN approach (DeepSignal) outperforms a common HMM approach (Nanopolish) in the incomplete data setting. Furthermore, we propose a novel hybrid HMM-DNN approach, amortized-HMM, that outperforms both the pure HMM and DNN approaches on 5mC calling when the training data are incomplete. This type of approach is expected to be useful for calling other base modifications such as 5-hydroxymethylcytosine and for the simultaneous calling of different modifications, settings in which complete training data are not likely to be available.
纳米孔测序平台与有监督的机器学习(ML)相结合,可有效检测 DNA 中的碱基修饰,如 5-甲基胞嘧啶(5mC)和 N6-甲基腺嘌呤(6mA)。这些基于 ML 的纳米孔呼叫器通常是在涵盖所有可能的 DNA [公式:见正文]-聚合物背景上的所有修饰的数据--一个完整的训练数据集上进行训练的。然而,随着纳米孔技术被推向越来越多的表观遗传修饰,这种完整的训练数据将难以获得。纳米孔调用历来使用隐马尔可夫模型(HMMs),由于其独立的发射分布,HMMs 无法成功调用训练期间未见的[公式:见正文]-mer 背景。然而,深度神经网络(DNN)在不同语境中共享参数,正越来越多地被用作调用器,其性能往往优于 HMM。按理说,DNN 方法应该能够更好地泛化到未见[公式:见正文]的语境中。事实上,我们在本文中证明,在不完整数据环境中,常见的 DNN 方法(DeepSignal)优于常见的 HMM 方法(Nanopolish)。此外,我们还提出了一种新颖的 HMM-DNN 混合方法(amortized-HMM),在训练数据不完整的情况下,该方法在 5mC 调用方面的表现优于纯 HMM 和 DNN 方法。这种方法有望用于调用其他碱基修饰,如 5-hydroxymethylcytosine 以及同时调用不同的修饰,因为在这种情况下不可能获得完整的训练数据。
{"title":"Effective training of nanopore callers for epigenetic marks with limited labelled data.","authors":"Brian Yao, Chloe Hsu, Gal Goldner, Yael Michaeli, Yuval Ebenstein, Jennifer Listgarten","doi":"10.1098/rsob.230449","DOIUrl":"10.1098/rsob.230449","url":null,"abstract":"<p><p>Nanopore sequencing platforms combined with supervised machine learning (ML) have been effective at detecting base modifications in DNA such as 5-methylcytosine (5mC) and N6-methyladenine (6mA). These ML-based nanopore callers have typically been trained on data that span all modifications on all possible DNA [Formula: see text]-mer backgrounds-a <i>complete</i> training dataset. However, as nanopore technology is pushed to more and more epigenetic modifications, such complete training data will not be feasible to obtain. Nanopore calling has historically been performed with hidden Markov models (HMMs) that cannot make successful calls for [Formula: see text]-mer contexts not seen during training because of their independent emission distributions. However, deep neural networks (DNNs), which share parameters across contexts, are increasingly being used as callers, often outperforming their HMM cousins. It stands to reason that a DNN approach should be able to better generalize to unseen [Formula: see text]-mer contexts. Indeed, herein we demonstrate that a common DNN approach (DeepSignal) outperforms a common HMM approach (Nanopolish) in the incomplete data setting. Furthermore, we propose a novel hybrid HMM-DNN approach, amortized-HMM, that outperforms both the pure HMM and DNN approaches on 5mC calling when the training data are incomplete. This type of approach is expected to be useful for calling other base modifications such as 5-hydroxymethylcytosine and for the simultaneous calling of different modifications, settings in which complete training data are not likely to be available.</p>","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-06-19DOI: 10.1098/rsob.240113
Tania Aerts, Anneleen Boonen, Lieve Geenen, Anne Stulens, Luca Masin, Anna Pancho, Annick Francis, Elise Pepermans, Geert Baggerman, Frans Van Roy, Markus Wöhr, Eve Seuntjens
Autism spectrum disorder (ASD) is a group of neurodevelopmental conditions associated with deficits in social interaction and communication, together with repetitive behaviours. The cell adhesion molecule protocadherin10 (PCDH10) is linked to ASD in humans. Pcdh10 is expressed in the nervous system during embryonic and early postnatal development and is important for neural circuit formation. In mice, strong expression of Pcdh10 in the ganglionic eminences and in the basolateral complex (BLC) of the amygdala was observed at mid and late embryonic stages, respectively. Both inhibitory and excitatory neurons expressed Pcdh10 in the BLC at perinatal stages and vocalization-related genes were enriched in Pcdh10-expressing neurons in adult mice. An epitope-tagged Pcdh10-HAV5 mouse line revealed endogenous interactions of PCDH10 with synaptic proteins in the young postnatal telencephalon. Nuanced socio-affective communication changes in call emission rates, acoustic features and call subtype clustering were primarily observed in heterozygous pups of a conditional knockout (cKO) with selective deletion of Pcdh10 in Gsh2-lineage interneurons. These changes were less prominent in heterozygous ubiquitous Pcdh10 KO pups, suggesting that altered anxiety levels associated with Gsh2-lineage interneuron functioning might drive the behavioural effects. Together, loss of Pcdh10 specifically in interneurons contributes to behavioural alterations in socio-affective communication with relevance to ASD.
自闭症谱系障碍(ASD)是一组与社交互动和沟通障碍以及重复行为有关的神经发育疾病。细胞粘附分子原粘连蛋白10(PCDH10)与人类自闭症谱系障碍有关。Pcdh10 在胚胎和出生后早期发育过程中在神经系统中表达,对神经回路的形成非常重要。在小鼠胚胎发育中期和晚期,分别在神经节突起和杏仁核基底复合体(BLC)中观察到 Pcdh10 的强表达。在围产期,抑制性神经元和兴奋性神经元都在BLC中表达Pcdh10,成年小鼠的Pcdh10表达神经元中富含发声相关基因。表位标记的Pcdh10-HAV5小鼠品系揭示了PCDH10与出生后幼年端脑中突触蛋白的内源性相互作用。在Gsh2线型中间神经元中选择性缺失Pcdh10的条件性基因敲除(cKO)杂合子幼鼠中,主要观察到了叫声发射率、声学特征和叫声亚型集群方面的细微社会情感交流变化。这些变化在杂合泛在 Pcdh10 KO 幼鼠中并不那么突出,这表明与 Gsh2 线型中间神经元功能相关的焦虑水平的改变可能会驱动行为效应。总之,Pcdh10在中间神经元中的特异性缺失导致了与自闭症相关的社会情感交流的行为改变。
{"title":"Altered socio-affective communication and amygdala development in mice with protocadherin10-deficient interneurons.","authors":"Tania Aerts, Anneleen Boonen, Lieve Geenen, Anne Stulens, Luca Masin, Anna Pancho, Annick Francis, Elise Pepermans, Geert Baggerman, Frans Van Roy, Markus Wöhr, Eve Seuntjens","doi":"10.1098/rsob.240113","DOIUrl":"10.1098/rsob.240113","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) is a group of neurodevelopmental conditions associated with deficits in social interaction and communication, together with repetitive behaviours. The cell adhesion molecule protocadherin10 (<i>PCDH10</i>) is linked to ASD in humans. <i>Pcdh10</i> is expressed in the nervous system during embryonic and early postnatal development and is important for neural circuit formation. In mice, strong expression of <i>Pcdh10</i> in the ganglionic eminences and in the basolateral complex (BLC) of the amygdala was observed at mid and late embryonic stages, respectively. Both inhibitory and excitatory neurons expressed <i>Pcdh10</i> in the BLC at perinatal stages and vocalization-related genes were enriched in <i>Pcdh10</i>-expressing neurons in adult mice. An epitope-tagged <i>Pcdh10</i>-HAV5 mouse line revealed endogenous interactions of PCDH10 with synaptic proteins in the young postnatal telencephalon. Nuanced socio-affective communication changes in call emission rates, acoustic features and call subtype clustering were primarily observed in heterozygous pups of a conditional knockout (cKO) with selective deletion of <i>Pcdh10</i> in <i>Gsh2</i>-lineage interneurons. These changes were less prominent in heterozygous ubiquitous <i>Pcdh10</i> KO pups, suggesting that altered anxiety levels associated with <i>Gsh2</i>-lineage interneuron functioning might drive the behavioural effects. Together, loss of <i>Pcdh10</i> specifically in interneurons contributes to behavioural alterations in socio-affective communication with relevance to ASD.</p>","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141420295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-06-12DOI: 10.1098/rsob.240035
M Gyimesi, R K Okolicsanyi, L M Haupt
Neurodegenerative diseases, particularly Alzheimer's disease (AD), pose a significant challenge in ageing populations. Our current understanding indicates that the onset of toxic amyloid and tau protein pathologies initiates disease progression. However, existing treatments targeting these hallmark symptoms offer symptomatic relief without halting disease advancement. This review offers an alternative perspective on AD, centring on impaired adult hippocampal neurogenesis (AHN) as a potential early aetiological factor. By delving into the intricate molecular events during the initial stages of AD (Braak Stages I-III), a novel hypothesis is presented, interweaving the roles of Notch signalling and heparan sulfate proteoglycans (HSPGs) in compromised AHN. While acknowledging the significance of the amyloid and tau hypotheses, it calls for further exploration beyond these paradigms, suggesting the potential of altered HS sulfation patterns in AD initiation. Future directions propose more detailed investigations into early HS aggregation, aberrant sulfation patterns and examination of their temporal relationship with tau hyperphosphorylation. In challenging the conventional 'triggers' of AD and urging their reconsideration as symptoms, this review advocates an alternative approach to understanding this disease, offering new avenues of investigation into the intricacies of AD pathogenesis.
神经退行性疾病,尤其是阿尔茨海默病(AD),给老龄人口带来了巨大挑战。我们目前的认识表明,淀粉样蛋白和 tau 蛋白的毒性病理变化是疾病进展的起因。然而,针对这些标志性症状的现有治疗方法只能缓解症状,却无法阻止疾病的发展。这篇综述从另一个角度探讨了注意力缺失症,将受损的成人海马神经元生成(AHN)作为潜在的早期致病因素。通过深入研究 AD 初期阶段(Braak 阶段 I-III)错综复杂的分子事件,本文提出了一个新的假设,将 Notch 信号和硫酸肝素蛋白多糖(HSPGs)在受损的 AHN 中的作用交织在一起。在承认淀粉样蛋白假说和 tau 假说的重要性的同时,该假说要求进一步探索这些假说之外的其他假说,并提出了在 AD 发病过程中改变 HS 硫酸化模式的可能性。未来的研究方向是对早期HS聚集、异常硫酸化模式进行更详细的调查,并研究它们与tau过度磷酸化的时间关系。这篇综述对AD的传统 "诱发因素 "提出了质疑,并敦促人们重新考虑它们作为症状的作用,它提倡用另一种方法来理解这种疾病,为研究AD发病机制的复杂性提供了新的途径。
{"title":"Beyond amyloid and tau: rethinking Alzheimer's disease through less explored avenues.","authors":"M Gyimesi, R K Okolicsanyi, L M Haupt","doi":"10.1098/rsob.240035","DOIUrl":"10.1098/rsob.240035","url":null,"abstract":"<p><p>Neurodegenerative diseases, particularly Alzheimer's disease (AD), pose a significant challenge in ageing populations. Our current understanding indicates that the onset of toxic amyloid and tau protein pathologies initiates disease progression. However, existing treatments targeting these hallmark symptoms offer symptomatic relief without halting disease advancement. This review offers an alternative perspective on AD, centring on impaired adult hippocampal neurogenesis (AHN) as a potential early aetiological factor. By delving into the intricate molecular events during the initial stages of AD (Braak Stages I-III), a novel hypothesis is presented, interweaving the roles of Notch signalling and heparan sulfate proteoglycans (HSPGs) in compromised AHN. While acknowledging the significance of the amyloid and tau hypotheses, it calls for further exploration beyond these paradigms, suggesting the potential of altered HS sulfation patterns in AD initiation. Future directions propose more detailed investigations into early HS aggregation, aberrant sulfation patterns and examination of their temporal relationship with tau hyperphosphorylation. In challenging the conventional 'triggers' of AD and urging their reconsideration as symptoms, this review advocates an alternative approach to understanding this disease, offering new avenues of investigation into the intricacies of AD pathogenesis.</p>","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-06-12DOI: 10.1098/rsob.240025
Daniel Ballmer, William Carter, Jolien J E van Hooff, Eelco C Tromer, Midori Ishii, Patryk Ludzia, Bungo Akiyoshi
Faithful transmission of genetic material is crucial for the survival of all organisms. In many eukaryotes, a feedback control mechanism called the spindle checkpoint ensures chromosome segregation fidelity by delaying cell cycle progression until all chromosomes achieve proper attachment to the mitotic spindle. Kinetochores are the macromolecular complexes that act as the interface between chromosomes and spindle microtubules. While most eukaryotes have canonical kinetochore proteins that are widely conserved, kinetoplastids such as Trypanosoma brucei have a seemingly unique set of kinetochore proteins including KKT1-25. It remains poorly understood how kinetoplastids regulate cell cycle progression or ensure chromosome segregation fidelity. Here, we report a crystal structure of the C-terminal domain of KKT14 from Apiculatamorpha spiralis and uncover that it is a pseudokinase. Its structure is most similar to the kinase domain of a spindle checkpoint protein Bub1. In addition, KKT14 has a putative ABBA motif that is present in Bub1 and its paralogue BubR1. We also find that the N-terminal part of KKT14 interacts with KKT15, whose WD40 repeat beta-propeller is phylogenetically closely related to a direct interactor of Bub1/BubR1 called Bub3. Our findings indicate that KKT14-KKT15 are divergent orthologues of Bub1/BubR1-Bub3, which promote accurate chromosome segregation in trypanosomes.
{"title":"Kinetoplastid kinetochore proteins KKT14-KKT15 are divergent Bub1/BubR1-Bub3 proteins.","authors":"Daniel Ballmer, William Carter, Jolien J E van Hooff, Eelco C Tromer, Midori Ishii, Patryk Ludzia, Bungo Akiyoshi","doi":"10.1098/rsob.240025","DOIUrl":"10.1098/rsob.240025","url":null,"abstract":"<p><p>Faithful transmission of genetic material is crucial for the survival of all organisms. In many eukaryotes, a feedback control mechanism called the spindle checkpoint ensures chromosome segregation fidelity by delaying cell cycle progression until all chromosomes achieve proper attachment to the mitotic spindle. Kinetochores are the macromolecular complexes that act as the interface between chromosomes and spindle microtubules. While most eukaryotes have canonical kinetochore proteins that are widely conserved, kinetoplastids such as <i>Trypanosoma brucei</i> have a seemingly unique set of kinetochore proteins including KKT1-25. It remains poorly understood how kinetoplastids regulate cell cycle progression or ensure chromosome segregation fidelity. Here, we report a crystal structure of the C-terminal domain of KKT14 from <i>Apiculatamorpha spiralis</i> and uncover that it is a pseudokinase. Its structure is most similar to the kinase domain of a spindle checkpoint protein Bub1. In addition, KKT14 has a putative ABBA motif that is present in Bub1 and its paralogue BubR1. We also find that the N-terminal part of KKT14 interacts with KKT15, whose WD40 repeat beta-propeller is phylogenetically closely related to a direct interactor of Bub1/BubR1 called Bub3. Our findings indicate that KKT14-KKT15 are divergent orthologues of Bub1/BubR1-Bub3, which promote accurate chromosome segregation in trypanosomes.</p>","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-06-19DOI: 10.1098/rsob.230363
Maya Michon, Andreas Müller-Schiffmann, Anuradha F Lingappa, Shao Feng Yu, Li Du, Fred Deiter, Sean Broce, Suguna Mallesh, Jackelyn Crabtree, Usha F Lingappa, Amanda Macieik, Lisa Müller, Philipp Niklas Ostermann, Marcel Andrée, Ortwin Adams, Heiner Schaal, Robert J Hogan, Ralph A Tripp, Umesh Appaiah, Sanjeev K Anand, Thomas W Campi, Michael J Ford, Jonathan C Reed, Jim Lin, Olayemi Akintunde, Kiel Copeland, Christine Nichols, Emma Petrouski, Ana R Moreira, I-Ting Jiang, Nicholas DeYarman, Ian Brown, Sharon Lau, Ilana Segal, Danielle Goldsmith, Shi Hong, Vinod Asundi, Erica M Briggs, Ngwe Sin Phyo, Markus Froehlich, Bruce Onisko, Kent Matlack, Debendranath Dey, Jaisri R Lingappa, Dharma M Prasad, Anatoliy Kitaygorodskyy, Dennis Solas, Homer Boushey, John Greenland, Satish Pillai, Michael K Lo, Joel M Montgomery, Christina F Spiropoulou, Carsten Korth, Suganya Selvarajah, Kumar Paulvannan, Vishwanath R Lingappa
We present a novel small molecule antiviral chemotype that was identified by an unconventional cell-free protein synthesis and assembly-based phenotypic screen for modulation of viral capsid assembly. Activity of PAV-431, a representative compound from the series, has been validated against infectious viruses in multiple cell culture models for all six families of viruses causing most respiratory diseases in humans. In animals, this chemotype has been demonstrated efficacious for porcine epidemic diarrhoea virus (a coronavirus) and respiratory syncytial virus (a paramyxovirus). PAV-431 is shown to bind to the protein 14-3-3, a known allosteric modulator. However, it only appears to target the small subset of 14-3-3 which is present in a dynamic multi-protein complex whose components include proteins implicated in viral life cycles and in innate immunity. The composition of this target multi-protein complex appears to be modified upon viral infection and largely restored by PAV-431 treatment. An advanced analog, PAV-104, is shown to be selective for the virally modified target, thereby avoiding host toxicity. Our findings suggest a new paradigm for understanding, and drugging, the host-virus interface, which leads to a new clinical therapeutic strategy for treatment of respiratory viral disease.
{"title":"A pan-respiratory antiviral chemotype targeting a transient host multi-protein complex.","authors":"Maya Michon, Andreas Müller-Schiffmann, Anuradha F Lingappa, Shao Feng Yu, Li Du, Fred Deiter, Sean Broce, Suguna Mallesh, Jackelyn Crabtree, Usha F Lingappa, Amanda Macieik, Lisa Müller, Philipp Niklas Ostermann, Marcel Andrée, Ortwin Adams, Heiner Schaal, Robert J Hogan, Ralph A Tripp, Umesh Appaiah, Sanjeev K Anand, Thomas W Campi, Michael J Ford, Jonathan C Reed, Jim Lin, Olayemi Akintunde, Kiel Copeland, Christine Nichols, Emma Petrouski, Ana R Moreira, I-Ting Jiang, Nicholas DeYarman, Ian Brown, Sharon Lau, Ilana Segal, Danielle Goldsmith, Shi Hong, Vinod Asundi, Erica M Briggs, Ngwe Sin Phyo, Markus Froehlich, Bruce Onisko, Kent Matlack, Debendranath Dey, Jaisri R Lingappa, Dharma M Prasad, Anatoliy Kitaygorodskyy, Dennis Solas, Homer Boushey, John Greenland, Satish Pillai, Michael K Lo, Joel M Montgomery, Christina F Spiropoulou, Carsten Korth, Suganya Selvarajah, Kumar Paulvannan, Vishwanath R Lingappa","doi":"10.1098/rsob.230363","DOIUrl":"10.1098/rsob.230363","url":null,"abstract":"<p><p>We present a novel small molecule antiviral chemotype that was identified by an unconventional cell-free protein synthesis and assembly-based phenotypic screen for modulation of viral capsid assembly. Activity of PAV-431, a representative compound from the series, has been validated against infectious viruses in multiple cell culture models for all six families of viruses causing most respiratory diseases in humans. In animals, this chemotype has been demonstrated efficacious for porcine epidemic diarrhoea virus (a coronavirus) and respiratory syncytial virus (a paramyxovirus). PAV-431 is shown to bind to the protein 14-3-3, a known allosteric modulator. However, it only appears to target the small subset of 14-3-3 which is present in a dynamic multi-protein complex whose components include proteins implicated in viral life cycles and in innate immunity. The composition of this target multi-protein complex appears to be modified upon viral infection and largely restored by PAV-431 treatment. An advanced analog, PAV-104, is shown to be selective for the virally modified target, thereby avoiding host toxicity. Our findings suggest a new paradigm for understanding, and drugging, the host-virus interface, which leads to a new clinical therapeutic strategy for treatment of respiratory viral disease.</p>","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141420294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Traditional medication and alternative therapies have long been used to treat breast cancer. One of the main problems with current treatments is that there is an increase in drug resistance in the cancer cells owing to genetic differences such as mutational changes, epigenetic changes and miRNA (microRNA) alterations such as miR-1246, miR-298, miR-27b and miR-33a, along with epigenetic modifications, such as Histone3 acetylation and CCCTC-Binding Factor (CTCF) hypermethylation for drug resistance in breast cancer cell lines. Certain forms of conventional drug resistance have been linked to genetic changes in genes such as ABCB1, AKT, S100A8/A9, TAGLN2 and NPM. This review aims to explore the current approaches to counter breast cancer, the action mechanism, along with novel therapeutic methods endowing potential drug resistance. The investigation of novel therapeutic approaches sheds light on the phenomenon of drug resistance including genetic variations that impact distinct forms of oestrogen receptor (ER) cancer, genetic changes, epigenetics-reported resistance and their identification in patients. Long-term effective therapy for breast cancer includes selective oestrogen receptor modulators, selective oestrogen receptor degraders and genetic variations, such as mutations in nuclear genes, epigenetic modifications and miRNA alterations in target proteins. Novel research addressing combinational therapies including maytansine, photodynamic therapy, guajadiol, talazoparib, COX2 inhibitors and miRNA 1246 inhibitors have been developed to improve patient survival rates.
{"title":"Oestrogen receptor positive breast cancer and its embedded mechanism: breast cancer resistance to conventional drugs and related therapies, a review.","authors":"Manu Yadav, Ishita Vaishkiar, Ananya Sharma, Akanksha Shukla, Aradhana Mohan, Madhuri Girdhar, Anil Kumar, Tabarak Malik, Anand Mohan","doi":"10.1098/rsob.230272","DOIUrl":"10.1098/rsob.230272","url":null,"abstract":"<p><p>Traditional medication and alternative therapies have long been used to treat breast cancer. One of the main problems with current treatments is that there is an increase in drug resistance in the cancer cells owing to genetic differences such as mutational changes, epigenetic changes and miRNA (microRNA) alterations such as miR-1246, miR-298, miR-27b and miR-33a, along with epigenetic modifications, such as Histone3 acetylation and CCCTC-Binding Factor (CTCF) hypermethylation for drug resistance in breast cancer cell lines. Certain forms of conventional drug resistance have been linked to genetic changes in genes such as <i>ABCB1</i>, <i>AKT</i>, <i>S100A8/A9</i>, <i>TAGLN2</i> and <i>NPM</i>. This review aims to explore the current approaches to counter breast cancer, the action mechanism, along with novel therapeutic methods endowing potential drug resistance. The investigation of novel therapeutic approaches sheds light on the phenomenon of drug resistance including genetic variations that impact distinct forms of oestrogen receptor (ER) cancer, genetic changes, epigenetics-reported resistance and their identification in patients. Long-term effective therapy for breast cancer includes selective oestrogen receptor modulators, selective oestrogen receptor degraders and genetic variations, such as mutations in nuclear genes, epigenetic modifications and miRNA alterations in target proteins. Novel research addressing combinational therapies including maytansine, photodynamic therapy, guajadiol, talazoparib, COX2 inhibitors and miRNA 1246 inhibitors have been developed to improve patient survival rates.</p>","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141420298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01Epub Date: 2024-05-15DOI: 10.1098/rsob.240018
Rosemary A Bamford, Amila Zuko, Madeline Eve, Jan J Sprengers, Harm Post, Renske L R E Taggenbrock, Dominique Fäβler, Annika Mehr, Owen J R Jones, Aurimas Kudzinskas, Josan Gandawijaya, Ulrike C Müller, Martien J H Kas, J Peter H Burbach, Asami Oguro-Ando
The neuronal cell adhesion molecule contactin-4 (CNTN4) is genetically associated with autism spectrum disorder (ASD) and other psychiatric disorders. Cntn4-deficient mouse models have previously shown that CNTN4 plays important roles in axon guidance and synaptic plasticity in the hippocampus. However, the pathogenesis and functional role of CNTN4 in the cortex has not yet been investigated. Our study found a reduction in cortical thickness in the motor cortex of Cntn4-/- mice, but cortical cell migration and differentiation were unaffected. Significant morphological changes were observed in neurons in the M1 region of the motor cortex, indicating that CNTN4 is also involved in the morphology and spine density of neurons in the motor cortex. Furthermore, mass spectrometry analysis identified an interaction partner for CNTN4, confirming an interaction between CNTN4 and amyloid-precursor protein (APP). Knockout human cells for CNTN4 and/or APP revealed a relationship between CNTN4 and APP. This study demonstrates that CNTN4 contributes to cortical development and that binding and interplay with APP controls neural elongation. This is an important finding for understanding the physiological function of APP, a key protein for Alzheimer's disease. The binding between CNTN4 and APP, which is involved in neurodevelopment, is essential for healthy nerve outgrowth.
{"title":"CNTN4 modulates neural elongation through interplay with APP.","authors":"Rosemary A Bamford, Amila Zuko, Madeline Eve, Jan J Sprengers, Harm Post, Renske L R E Taggenbrock, Dominique Fäβler, Annika Mehr, Owen J R Jones, Aurimas Kudzinskas, Josan Gandawijaya, Ulrike C Müller, Martien J H Kas, J Peter H Burbach, Asami Oguro-Ando","doi":"10.1098/rsob.240018","DOIUrl":"10.1098/rsob.240018","url":null,"abstract":"<p><p>The neuronal cell adhesion molecule contactin-4 (<i>CNTN4</i>) is genetically associated with autism spectrum disorder (ASD) and other psychiatric disorders. <i>Cntn4</i>-deficient mouse models have previously shown that CNTN4 plays important roles in axon guidance and synaptic plasticity in the hippocampus. However, the pathogenesis and functional role of CNTN4 in the cortex has not yet been investigated. Our study found a reduction in cortical thickness in the motor cortex of <i>Cntn4</i> <sup>-/-</sup> mice, but cortical cell migration and differentiation were unaffected. Significant morphological changes were observed in neurons in the M1 region of the motor cortex, indicating that CNTN4 is also involved in the morphology and spine density of neurons in the motor cortex. Furthermore, mass spectrometry analysis identified an interaction partner for CNTN4, confirming an interaction between CNTN4 and amyloid-precursor protein (APP). Knockout human cells for CNTN4 and/or APP revealed a relationship between CNTN4 and APP. This study demonstrates that CNTN4 contributes to cortical development and that binding and interplay with APP controls neural elongation. This is an important finding for understanding the physiological function of APP, a key protein for Alzheimer's disease. The binding between CNTN4 and APP, which is involved in neurodevelopment, is essential for healthy nerve outgrowth.</p>","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140923008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}