Open BiologyPub Date : 2024-11-01Epub Date: 2024-11-06DOI: 10.1098/rsob.240100
Vranda Garg, Selina André, Luisa Heyer, Gudrun Kracht, Torben Ruhwedel, Patricia Scholz, Till Ischebeck, Hauke B Werner, Christian Dullin, Jacob Engelmann, Wiebke Möbius, Martin C Göpfert, Roland Dosch, Bart R H Geurten
{"title":"Axon demyelination and degeneration in a zebrafish <i>spastizin</i> model of hereditary spastic paraplegia.","authors":"Vranda Garg, Selina André, Luisa Heyer, Gudrun Kracht, Torben Ruhwedel, Patricia Scholz, Till Ischebeck, Hauke B Werner, Christian Dullin, Jacob Engelmann, Wiebke Möbius, Martin C Göpfert, Roland Dosch, Bart R H Geurten","doi":"10.1098/rsob.240100","DOIUrl":"10.1098/rsob.240100","url":null,"abstract":"<p><p>Hereditary spastic paraplegias (HSPs) are a diverse set of neurological disorders characterized by progressive spasticity and weakness in the lower limbs caused by damage to the axons of the corticospinal tract. More than 88 genetic mutations have been associated with HSP, yet the mechanisms underlying these disorders are not well understood. We replicated the pathophysiology of one form of HSP known as spastic paraplegia 15 (SPG15) in zebrafish. This disorder is caused in humans by mutations in the <i>ZFYVE26</i> gene, which codes for a protein called SPASTIZIN. We show that, in zebrafish, the significant reduction of Spastizin caused degeneration of large motor neurons. Motor neuron degeneration is associated with axon demyelination in the spinal cord and impaired locomotion in the <i>spastizin</i> mutants. Our findings reveal that the reduction in Spastizin compromises axonal integrity and affects the myelin sheath, ultimately recapitulating the pathophysiology of HSPs.</p>","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":"14 11","pages":"240100"},"PeriodicalIF":4.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583961","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}
{"title":"Correction to: 'The telomeric protein AKTIP interacts with A- and B-type lamins and is involved in regulation of cellular senescence' (2016), by Burla <i>et al.</i>","authors":"Romina Burla, Mariateresa Carcuro, Mattia La Torre, Federica Fratini, Marco Crescenzi, Maria Rosaria D'Apice, Paola Spitalieri, Grazia Daniela Raffa, Letizia Astrologo, Giovanna Lattanzi, Enrico Cundari, Domenico Raimondo, Annamaria Biroccio, Maurizio Gatti, Isabella Saggio","doi":"10.1098/rsob.240314","DOIUrl":"10.1098/rsob.240314","url":null,"abstract":"","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":"14 11","pages":"240314"},"PeriodicalIF":4.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11557223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142625348","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}
Open BiologyPub Date : 2024-11-01Epub Date: 2024-11-13DOI: 10.1098/rsob.240159
Renee Dale, Rebecca Mosher
{"title":"Mathematical model of RNA-directed DNA methylation predicts tuning of negative feedback required for stable maintenance.","authors":"Renee Dale, Rebecca Mosher","doi":"10.1098/rsob.240159","DOIUrl":"10.1098/rsob.240159","url":null,"abstract":"<p><p>RNA-directed DNA methylation (RdDM) is a plant-specific de novo methylation pathway that is responsible for maintenance of asymmetric methylation (CHH, H = A, T or G) in euchromatin. Loci with CHH methylation produce 24 nucleotide (nt) short interfering (si) RNAs. These siRNAs direct additional CHH methylation to the locus, maintaining methylation states through DNA replication. To understand the necessary conditions to produce stable methylation, we developed a stochastic mathematical model of RdDM. The model describes DNA target search by siRNAs derived from CHH methylated loci bound by an Argonaute. Methylation reinforcement occurs either throughout the cell cycle (steady) or immediately following replication (bursty). We compare initial and final methylation distributions to determine simulation conditions that produce stable methylation. We apply this method to the low CHH methylation case. The resulting model predicts that siRNA production must be linearly proportional to methylation levels, that bursty reinforcement is more stable and that slightly higher levels of siRNA production are required for searching DNA, compared to RNA. Unlike CG methylation, which typically exhibits bi-modality with loci having either 100% or 0% methylation, CHH methylation exists across a range. Our model predicts that careful tuning of the negative feedback in the system is required to enable stable maintenance.</p>","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":"14 11","pages":"240159"},"PeriodicalIF":4.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11557233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623489","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}
{"title":"Cebpa is required for haematopoietic stem and progenitor cell generation and maintenance in zebrafish.","authors":"Kemin Chen, Jieyi Wu, Yuxian Zhang, Wei Liu, Xiaohui Chen, Wenqing Zhang, Zhibin Huang","doi":"10.1098/rsob.240215","DOIUrl":"10.1098/rsob.240215","url":null,"abstract":"<p><p>The CCAAT enhancer binding protein alpha (CEBPA) is crucial for myeloid differentiation and the balance of haematopoietic stem and progenitor cell (HSPC) quiescence and self-renewal, and its dysfunction can drive leukemogenesis. However, its role in HSPC generation has not been fully elucidated. Here, we utilized various zebrafish <i>cebpa</i> mutants to investigate the function of Cebpa in the HSPC compartment. Co-localization analysis showed that <i>cebpa</i> expression is enriched in nascent HSPCs. Complete loss of Cebpa function resulted in a significant reduction in early HSPC generation and the overall HSPC pool during embryonic haematopoiesis. Interestingly, while myeloid differentiation was impaired in <i>cebpa</i> N-terminal mutants expressing the truncated zP30 protein, the number of HSPCs was not affected, indicating a redundant role of Cebpa P42 and P30 isoforms in HSPC development. Additionally, epistasis experiments confirmed that Cebpa functions downstream of Runx1 to regulate HSPC emergence. Our findings uncover a novel role of Cebpa isoforms in HSPC generation and maintenance, and provide new insights into HSPC development.</p>","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":"14 11","pages":"240215"},"PeriodicalIF":4.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583963","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}
Open BiologyPub Date : 2024-11-01Epub Date: 2024-11-20DOI: 10.1098/rsob.240251
Sarka Novotna, Lorena Agostini Maia, Katarzyna Anna Radaszkiewicz, Pavel Roudnicky, Jakub Harnos
{"title":"Linking planar polarity signalling to actomyosin contractility during vertebrate neurulation.","authors":"Sarka Novotna, Lorena Agostini Maia, Katarzyna Anna Radaszkiewicz, Pavel Roudnicky, Jakub Harnos","doi":"10.1098/rsob.240251","DOIUrl":"https://doi.org/10.1098/rsob.240251","url":null,"abstract":"<p><p>Actomyosin contractility represents an ancient feature of eukaryotic cells participating in many developmental and homeostasis events, including tissue morphogenesis, muscle contraction and cell migration, with dysregulation implicated in various pathological conditions, such as cancer. At the molecular level, actomyosin comprises actin bundles and myosin motor proteins that are sensitive to posttranslational modifications like phosphorylation. While the molecular components of actomyosin are well understood, the coordination of contractility by extracellular and intracellular signals, particularly from cellular signalling pathways, remains incompletely elucidated. This study focuses on WNT/planar cell polarity (PCP) signalling, previously associated with actomyosin contractility during vertebrate neurulation. Our investigation reveals that the main cytoplasmic PCP proteins, Prickle and Dishevelled, interact with key actomyosin components such as myosin light chain 9 (MLC9), leading to its phosphorylation and localized activation. Using proteomics and microscopy approaches, we demonstrate that both PCP proteins actively control actomyosin contractility through Rap1 small GTPases in relevant <i>in vitro</i> and <i>in vivo</i> models. These findings unveil a novel mechanism of how PCP signalling regulates actomyosin contractility through MLC9 and Rap1 that is relevant to vertebrate neurulation.</p>","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":"14 11","pages":"240251"},"PeriodicalIF":4.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Open BiologyPub Date : 2024-11-01Epub Date: 2024-11-13DOI: 10.1098/rsob.240109
Nishita Bhembre, Annalisa Paolino, Sooraj S Das, Sumasri Guntupalli, Laura R Fenlon, Victor Anggono
{"title":"Learning-induced remodelling of inhibitory synapses in the motor cortex.","authors":"Nishita Bhembre, Annalisa Paolino, Sooraj S Das, Sumasri Guntupalli, Laura R Fenlon, Victor Anggono","doi":"10.1098/rsob.240109","DOIUrl":"10.1098/rsob.240109","url":null,"abstract":"<p><p>Robust structural and functional plasticity occurs at excitatory synapses in the motor cortex in response to learning. It is well established that local spinogenesis and the subsequent maintenance of newly formed spines are crucial for motor learning. However, despite local synaptic inhibition being essential for shaping excitatory synaptic input, less is known about the structural rearrangement of inhibitory synapses following learning. In this study, we co-expressed the structural marker tdTomato and a mEmerald-tagged intrabody against gephyrin to visualize inhibitory synapses in layer 2/3 cortical neurons of wild-type CD1 mice. We found that a 1-day accelerated rotarod paradigm induced robust motor learning in male and female adult CD1 mice. Histological analyses revealed a significant increase in the surface area of gephyrin puncta in neurons within the motor cortex but not in the somatosensory cortex upon motor learning. Furthermore, this learning-induced reorganization of inhibitory synapses only occurred in dendritic shafts and not in the spines. These data suggest that learning induces experience-dependent remodelling of existing inhibitory synapses to fine-tune intrinsic plasticity and input-specific modulation of excitatory connections in the motor cortex.</p>","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":"14 11","pages":"240109"},"PeriodicalIF":4.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11557243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623536","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}
Open BiologyPub Date : 2024-11-01Epub Date: 2024-11-13DOI: 10.1098/rsob.240101
Esteban Moscoso-Romero, Sandra Moro, Alicia Duque, Francisco Yanguas, M-Henar Valdivieso
{"title":"Pck2 association with the plasma membrane and efficient response of the cell integrity pathway require regulation of PI4P homeostasis by exomer.","authors":"Esteban Moscoso-Romero, Sandra Moro, Alicia Duque, Francisco Yanguas, M-Henar Valdivieso","doi":"10.1098/rsob.240101","DOIUrl":"10.1098/rsob.240101","url":null,"abstract":"<p><p>Exomer is a protein complex that facilitates trafficking between the Golgi and the plasma membrane (PM). <i>Schizosaccharomyces pombe</i> exomer is composed of Cfr1 and Bch1, and we have found that full activation of the cell integrity pathway (CIP) in response to osmotic stress requires exomer. In the wild-type, the CIP activators Rgf1 (Rho1 GEF) and Pck2 (PKC homologue) and the MEK kinase Mkh1 localize in the PM, internalize after osmotic shock and re-localize after adaptation. This re-localization is inefficient in exomer mutants. Overexpression of the PM-associated 1-phosphatidylinositol 4-kinase <i>stt4+</i>, and deletion of the <i>nem1+</i> phosphatase suppress the defects in Pck2 dynamics in exomer mutants, but not their defect in CIP activation, demonstrating that exomer regulates CIP in additional ways. Exomer mutants accumulate PI4P in the TGN, and increasing the expression of the Golgi-associated 1-phosphatidylinositol 4-kinase <i>pik1+</i> suppresses their defect in Pck2 dynamics. These findings suggest that efficient PI4P transport from the Golgi to the PM requires exomer. Mutants lacking clathrin adaptors are defective in CIP activation, but not in Pck2 dynamics or in PI4P accumulation in the Golgi. Hence, traffic from the Golgi regulates CIP activation, and exomer participates in this regulation through an exclusive mechanism.</p>","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":"14 11","pages":"240101"},"PeriodicalIF":4.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623669","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}
Open BiologyPub Date : 2024-11-01Epub Date: 2024-11-06DOI: 10.1098/rsob.240190
Frances Blow, Kate Jeffrey, Franklin Wang-Ngai Chow, Inna A Nikonorova, Maureen M Barr, Atlanta G Cook, Bram Prevo, Dhanya K Cheerambathur, Amy H Buck
{"title":"SID-2 is a conserved extracellular vesicle protein that is not associated with environmental RNAi in parasitic nematodes.","authors":"Frances Blow, Kate Jeffrey, Franklin Wang-Ngai Chow, Inna A Nikonorova, Maureen M Barr, Atlanta G Cook, Bram Prevo, Dhanya K Cheerambathur, Amy H Buck","doi":"10.1098/rsob.240190","DOIUrl":"10.1098/rsob.240190","url":null,"abstract":"<p><p>In the free-living nematode <i>Caenorhabditis elegans,</i> the transmembrane protein SID-2 imports double-stranded RNA into intestinal cells to trigger systemic RNA interference (RNAi), allowing organisms to sense and respond to environmental cues such as the presence of pathogens. This process, known as environmental RNAi, has not been observed in the most closely related parasites that are also within clade V. Previous sequence-based searches failed to identify <i>sid-2</i> orthologues in available clade V parasite genomes. In this study, we identified <i>sid-2</i> orthologues in these parasites using genome synteny and protein structure-based comparison, following identification of a SID-2 orthologue in extracellular vesicles from the murine intestinal parasitic nematode <i>Heligmosomoides bakeri</i>. Expression of GFP-tagged <i>H. bakeri</i> SID-2 in <i>C. elegans</i> showed similar localization to the intestinal apical membrane as seen for GFP-tagged <i>C. elegans</i> SID-2, and further showed mobility in intestinal cells in vesicle-like structures. We tested the capacity of <i>H. bakeri</i> SID-2 to functionally complement environmental RNAi in a <i>C. elegans</i> SID-2 null mutant and show that <i>H. bakeri</i> SID-2 does not rescue the phenotype in this context. Our work identifies SID-2 as a highly abundant EV protein whose ancestral function may be unrelated to environmental RNAi, and rather highlights an association with extracellular vesicles in nematodes.</p>","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":"14 11","pages":"240190"},"PeriodicalIF":4.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583965","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}
Open BiologyPub Date : 2024-11-01Epub Date: 2024-11-20DOI: 10.1098/rsob.240079
Fernando González Ibáñez, Jared VanderZwaag, Jessica Deslauriers, Marie-Ève Tremblay
{"title":"Ultrastructural features of psychological stress resilience in the brain: a microglial perspective.","authors":"Fernando González Ibáñez, Jared VanderZwaag, Jessica Deslauriers, Marie-Ève Tremblay","doi":"10.1098/rsob.240079","DOIUrl":"https://doi.org/10.1098/rsob.240079","url":null,"abstract":"<p><p>Psychological stress is the major risk factor for major depressive disorder. Sustained stress causes changes in behaviour, brain connectivity and in its cells and organelles. Resilience to stress is understood as the ability to recover from stress in a positive way or the resistance to the negative effects of psychological stress. Microglia, the resident immune cells of the brain, are known players of stress susceptibility, but less is known about their role in stress resilience and the cellular changes involved. Ultrastructural analysis has been a useful tool in the study of microglia and their function across contexts of health and disease. Despite increased access to electron microscopy, the interpretation of electron micrographs remains much less accessible. In this review, we will first present microglia and the concepts of psychological stress susceptibility and resilience. Afterwards, we will describe ultrastructural analysis, notably of microglia, as a readout to study the mechanisms underlying psychological stress resilience. Lastly, we will cover nutritional ketosis as a therapeutic intervention that was shown to be effective in promoting psychological stress resilience as well as modifying microglial function and ultrastructure.</p>","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":"14 11","pages":"240079"},"PeriodicalIF":4.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"An endoplasmic reticulum localized acetyl-CoA transporter is required for efficient fatty acid synthesis in <i>Toxoplasma gondii</i>.","authors":"Biyun Qin, Bolin Fan, Yazhou Li, Yidan Wang, Bang Shen, Ningbo Xia","doi":"10.1098/rsob.240184","DOIUrl":"10.1098/rsob.240184","url":null,"abstract":"<p><p><i>Toxoplasma gondii</i> is an obligate intracellular parasite that can infect humans and diverse animals. Fatty acids are critical for the growth and proliferation of <i>T. gondii</i>, which has at least two pathways to synthesize fatty acids, including the type II de novo synthesis pathway in the apicoplast and the elongation pathway in the endoplasmic reticulum (ER). Acetyl-CoA is the key substrate for both fatty acid synthesis pathways. In the apicoplast, acetyl-CoA is mainly provided by the pyruvate dehydrogenase complex. However, how the ER acquires acetyl-CoA is not fully understood. Here, we identified a putative acetyl-CoA transporter (TgAT1) that localized to the ER of <i>T. gondii</i>. Deletion of TgAT1 impaired parasite growth and invasion <i>in vitro</i> and attenuated tachyzoite virulence <i>in vivo</i>. Metabolic tracing using <sup>13</sup>C-acetate found that loss of TgAT1 reduced the incorporation of <sup>13</sup>C into certain fatty acids, suggesting reduced activities of elongation. Truncation of AT1 was previously reported to confer resistance to the antimalarial compound GNF179 in <i>Plasmodium falciparum</i>. Interestingly, GNF179 had much weaker inhibitory effect on <i>Toxoplasma</i> than on <i>Plasmodium</i>. In addition, deletion of AT1 did not affect the susceptibility of <i>Toxoplasma</i> to GNF179, suggesting that this compound might be taken up differently or has different inhibitory mechanisms in these parasites. Together, our data show that TgAT1 has important roles for parasite growth and fatty acid synthesis, but its disruption does not confer GNF179 resistance in <i>T. gondii</i>.</p>","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":"14 11","pages":"240184"},"PeriodicalIF":4.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11557232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142625345","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}