PLoS Genetics最新文献

{"title":"From individuals to ancestries: Towards attributing trait variation to haplotypes.","authors":"Yaoling Yang, Daniel J Lawson","doi":"10.1371/journal.pgen.1011883","DOIUrl":"10.1371/journal.pgen.1011883","url":null,"abstract":"<p><p>Genome-wide association studies (GWAS) have revolutionized our understanding of the genetic basis of complex traits and diseases, but limitations in SNP-centric approaches to population stratification limit the resolution of fine-scale population structures. Here we consider the use of haplotypes to represent population structure, leveraging haplotype components (HCs) for an improved understanding of trait associations and adjustment for population stratification. Using data from the UK Biobank, we showed that HCs have stronger associations with a range of phenotypes than principal components (PCs) while containing more predictive power for birthplaces globally. In GWAS, HCs-correction identifies more genome-wide significant association signals for birthplace and lifestyle-related phenotypes, which are missed by PCs-corrected GWAS. Through thorough testing and simulation, we highlight challenges in performing ancestry-specific GWAS, underscoring the critical role of accurate local ancestry inference in studying admixed populations. We analyzed the haplotype structure of the UK Biobank in terms of 93 genetically-distinct populations, which enabled the computation of Ancestral Risk Scores (ARS) across 8 continental populations, providing insights into population-specific genetic risks for traits and diseases. By integrating haplotype information, this framework provides the potential to address challenges in population stratification, enhances GWAS resolution, and supports equitable health research by facilitating genetic studies in diverse populations.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 9","pages":"e1011883"},"PeriodicalIF":3.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12507255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variants in CALD1, ESRP1, and RBFOX1 are associated with orofacial cleft risk.","authors":"Jenna C Carlson, Xinyi Zhang, Zeynep Erdogan-Yildirim, Terri H Beaty, Azeez Butali, Carmen J Buxó, Lord J J Gowans, Jacqueline T Hecht, Ross E Long, Lina Moreno, Jeffrey C Murray, Ieda M Orioli, Carmencita Padilla, George L Wehby, Eleanor Feingold, Elizabeth J Leslie-Clarkson, Seth M Weinberg, Mary L Marazita, John R Shaffer","doi":"10.1371/journal.pgen.1011581","DOIUrl":"10.1371/journal.pgen.1011581","url":null,"abstract":"<p><p>Nonsyndromic orofacial clefts (OFCs) are common, heritable birth defects caused by both genetic and environmental risk factors. Despite the identification of many genetic loci harboring OFC-risk variants, there are many unknown genetic determinants of OFC. Furthermore, while the process of embryonic facial development is well characterized, the molecular mechanisms that underly it are not. This represents a major hurdle in understanding how disruptions in these biological processes result in OFC. Thus, we sought to identify novel OFC-risk loci through a genome-wide multi-ancestry study of five nested OFC phenotypes (isolated cleft lip [CLO], isolated cleft palate [CPO], cleft lip and palate [CLP], cleft lip with/without cleft palate [CL/P], and any cleft [ANY]) representing distinct cleft subtypes to identify subtype-specific signals and grouped types to maximize power to detect shared genetic effects. We performed genome-wide meta-analyses of these five OFC phenotypes from three cohorts totaling >14,000 individuals using METAL. In addition to replicating 13 known OFC-risk loci, we observed novel association in three regions: the 1p36.32 locus (lead variant rs584402, an intergenic variant, pCLO = 3.14e-8), the 7q33 locus (lead variant rs17168118, an intronic variant in CALD1, pCLP = 9.17e-9), and the 16p13.3 locus (lead variant rs77075754, an intronic variant in RBFOX1, pCL/P = 1.53e-9, pANY = 1.93e-9). We also observed a novel association within the known risk locus 8q22.1 that was independent of the previously reported signal (lead variant rs4735314, an intronic variant in ESRP1, pCLP = 1.07e-9, pCL/P = 3.88e-8). Next, we performed multi-tissue TWAS with s-MulTiXcan and identified four overlapping genes with significant genetically predicted transcription associated with OFC risk. These genes also overlapped the genome-wide significant association signals from the meta-analysis, including CALD1 and ESRP1 and known OFC-risk genes TANC2 and NTN1. Each of the newly reported loci has potential regulatory effects, including evidence of craniofacial enhancer activity, that offer new clues as to the molecule mechanisms underlying embryonic facial development.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 9","pages":"e1011581"},"PeriodicalIF":3.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12503292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"On the analysis of genetic association with long-read sequencing data.","authors":"Gengming He, Stephen W Scherer, Lisa J Strug","doi":"10.1371/journal.pgen.1011887","DOIUrl":"10.1371/journal.pgen.1011887","url":null,"abstract":"<p><p>Long-read sequencing (LRS) technologies have enhanced the ability to resolve complex genomic architecture and determine the 'phase' relationships of genetic variants over long distances. Although genome-wide association studies (GWAS) identify individual variants associated with complex traits, they do not typically account for whether multiple associated signals at a locus may act in cis or trans, or whether they reflect allelic heterogeneity. As a result, effects that arise specifically from phase relationships may remain hidden in analyses using short-read and microarray data. While the advent of LRS has enabled accurate measurement of phase in population cohorts, statistical methods that leverage phase in genetic association analysis remain underdeveloped. Here, we introduce the Regression on Phase (RoP) method, which directly models cis and trans phase effects between variants under a regression framework. In simulations, RoP outperforms genotype interaction tests that detect phase effects indirectly, and distinguishes in-cis from in-trans phase effects. We implemented RoP at two cystic fibrosis (CF) modifier loci discovered by GWAS. At the chromosome 7q35 trypsinogen locus, RoP confirmed that two variants contributed independently (allelic heterogeneity). At the SLC6A14 locus on chromosome X, phase analysis uncovered a coordinated regulatory mechanism in which a promoter variant modulates lung phenotypes in individuals with CF when acting in cis with a lung-specific enhancer (E2765449/enhD). This coordinated regulation was confirmed in functional studies. These findings highlight the potential of leveraging phase information from LRS in genetic association studies. Analyzing phase effects with RoP can provide deeper insights into the complex genetic architectures underlying disease phenotypes, ultimately guiding more informed functional investigations and potentially revealing new therapeutic targets.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 9","pages":"e1011887"},"PeriodicalIF":3.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single cell RNA-sequencing reveals no evidence for meiotic sex chromosome inactivation in the threespine stickleback fish.","authors":"Daniel E Shaw, Wynter D Ross, Alexis V Lambert, Michael A White","doi":"10.1371/journal.pgen.1011875","DOIUrl":"10.1371/journal.pgen.1011875","url":null,"abstract":"<p><p>Sex chromosomes often evolve unique patterns of gene expression during spermatogenesis. In many species, sex-linked genes are downregulated during meiosis in response to asynapsis of the heterogametic sex chromosome pair (meiotic sex chromosome inactivation; MSCI). This process has evolved convergently across many taxa with independently derived sex chromosomes. Our understanding how quickly MSCI can evolve and whether it is connected to the degree of sequence degeneration remains limited. Teleost fish are a noteworthy group to investigate MSCI because sex chromosomes have evolved repeatedly across species, often over short evolutionary timescales. Here, we investigate whether MSCI occurs in the threespine stickleback fish (Gasterosteus aculeatus), which have an X and Y chromosome that evolved less than 26 million years ago. Using single-cell RNA-seq, we found that the X and Y chromosomes do not have a signature of MSCI, maintaining gene expression across meiosis. Using immunofluorescence, we also show the threespine stickleback do not form a condensed sex body around the X and Y, a feature of MSCI in many species. We did not see patterns of gene content evolution documented in other species with MSCI. Y-linked ampliconic gene families were expressed across multiple stages of spermatogenesis, rather than being restricted to post-meiotic stages, like in mammals. Our work shows MSCI does not occur in the threespine stickleback fish and has not shaped the evolution of the Y chromosome. In addition, the absence of MSCI in the threespine stickleback suggests this process may not be a conserved feature of teleost fish, despite overall sequence degeneration and structural evolution of the Y chromosome, and argues for additional investigation in other species. We also observed testis-dependent differences in coding and expression evolution for X-linked genes, revealing evidence of testis specific faster-X effect and gene-by-gene dosage compensation.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 9","pages":"e1011875"},"PeriodicalIF":3.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12503298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic coupling of ROS generation and antioxidant synthesis by the GABA shunt pathway in myeloid-like blood progenitor cells of Drosophila.","authors":"Manisha Goyal, Sakshi Tiwari, Jagriti Arora, Bruce Cooper, Ramaswamy Subramanian, Tina Mukherjee","doi":"10.1371/journal.pgen.1011602","DOIUrl":"10.1371/journal.pgen.1011602","url":null,"abstract":"<p><p>Redox balance is crucial for normal development of stem and progenitor cells that reside in oxidative environments. In this study, we explore the mechanisms of redox homeostasis in such niches and show that myeloid-like blood progenitor cells of the Drosophila larval lymph gland, that generate reactive oxygen species (ROS), moderate it developmentally by de novo synthesizing glutathione (GSH) to ensure redox balance. During lymph gland development, as the blood-progenitor cells oxidize pyruvate via the TCA cycle leading to the generation of ROS, GABA-shunt restricts pyruvate dehydrogenase (PDH) activity and consequently TCA cycle flux. This moderation enables a metabolic rerouting of TCA-derived oxaloacetate (OAA) to pyruvate via gluconeogenesis, which is necessary to sustain serine levels, the rate-limiting precursor for de novo GSH synthesis. Disruption of GABA metabolism causes metabolic imbalance, marked by excessive PDH activity and heightened TCA cycle flux. This results in reduced OAA availability, impaired gluconeogenic capacity, and insufficient serine/GSH production, ultimately leading to ROS dysregulation. Overall, this study identifies a unique metabolic framework in blood progenitor cells, where the GABA shunt, by restraining PDH and TCA cycle activity, maintains ROS at developmental levels. By coupling TCA-derived metabolites to GSH production, this state enables the TCA cycle to support both ROS generation and ROS scavenging, ensuring the developmental roles of ROS while preserving progenitor homeostasis.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 9","pages":"e1011602"},"PeriodicalIF":3.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying genetic determinants of outer retinal function in mice using a large-scale gene-targeted screen.","authors":"Janine M Wotton, Mark P Krebs, Riccardo Sangermano, Jessica K Wong, Cynthia Smith, Amelia M Willett, Douglas Howell, Abby Jones, Catherine Witmeyer, Jacob P Lowy, Michael McFarland, Stephan A Murray, Robert E Braun, Patsy M Nishina, Eric A Pierce, Emily M Place, Kinga M Bujakowska, Neal S Peachey, Jacqueline K White","doi":"10.1371/journal.pgen.1011886","DOIUrl":"10.1371/journal.pgen.1011886","url":null,"abstract":"<p><p>Electroretinography (ERG) provides a noninvasive functional measure of multiple cell types of the outer retina. We conducted an ERG-based screen of 530 single-gene knockout mouse strains generated as part of the International Mouse Phenotyping Consortium, representing 2.5% of all protein-coding genes, to identify genetic variants affecting retinal function. We identified 30 strains with significantly altered ERG amplitudes. Two of the genes identified, Cfap418 and Syne2, have been previously reported with outer retinal dysfunction, thereby serving as internal controls that validate our screening protocol. Of the remaining 28 genes newly associated with altered retinal function, the majority lacked a contemporaneous histopathology correlate, highlighting the importance of ERG in early detection of functional abnormalities. A rare homozygous missense variant in FCHSD2, the human orthologue of one of the 28 genes identified, was found in a patient presenting with retinal degeneration that lacked a molecular diagnosis. This report represents a useful resource for future investigations into the molecular mechanisms driving inherited retinal diseases and demonstrates the power of large-scale ERG screening in identifying novel genetic determinants of retinal function.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 9","pages":"e1011886"},"PeriodicalIF":3.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12503315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polycomb repressive complexes 1 and 2 independently and dynamically regulate euchromatin during cerebellar neurodevelopment.","authors":"Aditya Parmar, Anjali Srinivasan, Lena Krockenberger, Abijith Augustine, Owin Gong, Addison C Bullard, Riya Kalra, Leya Ledvin, Dylan Pilz, Jonathan Tawil, Challana E Tea, Kelly C Wang, Olivia Urso, Larissa M Kaube, Ying Sun, Roman Sasik, Kyle J Gaulton, Kathleen M Fisch, Cole J Ferguson","doi":"10.1371/journal.pgen.1011843","DOIUrl":"10.1371/journal.pgen.1011843","url":null,"abstract":"<p><p>Polycomb Repressive Complexes (PRCs) are known for chemically modifying histones to compact chromatin structure and repress transcription. Broadly speaking, PRC1 monoubiquitinates histone 2A at lysine 119 (H2AK119ub), and PRC2 methylates histone H3 lysine 27 (H3K27me3, H3K27me2 and H3K27me1), but the scope and functions of these activities are complicated by a multiplicity of factors involving distinct cellular contexts and compositions of both complexes. Because epigenetic dysregulation is associated with neurodevelopmental disorders, but little is known about normal PRC activities in neurons, we used CUT&RUN to map PRC-dependent histone modifications in the mouse cerebellum at two postnatal timepoints (day 12 and 3 months). We find that H2AK119ub appears within both heterochromatin and euchromatin as the cerebellum matures, becoming enriched within active enhancers and promoters while being depleted from heterochromatin. Unexpectedly, the PRC1 product H2AK119ub appeared frequently without the accompaniment of the PRC2 product H3K27me3; leading to a much more dynamic chromatin state than when these two marks colocalized. Deposition of H2AK119ub at loci with the chromatin signature of active cis-regulatory elements tended to also gain the euchromatin-associated modifications H3K4me3 and H3K27ac during neurodevelopment. Importantly, deposition of H2AK119ub within both bivalent and H3K4me3-only promoters reduced transcription of downstream genes. The pattern of H2AK119ub deposition was specific to the cerebellum compared to liver and kidney. We then show that the PRC2 product H3K27me1 formed euchromatic zones that alternated with heterochromatic zones dominated by H3K27me3. Between the early and late timepoints H3K27me1 became enriched within a subset of expressed gene bodies and depleted from most other genes while remaining uncorrelated with the abundance of the corresponding mRNAs. Our data lead us to propose that deposition of H2AK119ub and H3K27me1 during cerebellar development likely fine-tunes the activity of cis-regulatory elements and transcription, respectively, and that PRC1 and PRC2 activities become uncoupled in the mature brain.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 9","pages":"e1011843"},"PeriodicalIF":3.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conserved Calcineurin A splice variants regulate both constitutive and experience-dependent behaviors through tissue-specific signaling.","authors":"Martina Rudgalvyte, Dominique A Glauser","doi":"10.1371/journal.pgen.1011884","DOIUrl":"10.1371/journal.pgen.1011884","url":null,"abstract":"<p><p>Calcineurin is a conserved, calcium-regulated phosphatase involved in various functions, including muscle physiology and nervous system activity. The Calcineurin A (CnA) catalytic subunit consists of a phosphatase region and a regulatory domain, which includes a Calcineurin B binding helix, a Calmodulin binding domain, and an auto-inhibitory domain, separated by linker regions (LR1 and LR2). CnA diversity is generated via the existence of paralogous genes and via alternative splicing, producing tissue-specific isoforms, whose functional significance is only partially understood. Our analyses reveal that the LR2 region is an alternative splicing hotspot conserved across paralogous genes and across species, from humans to nematodes. To investigate LR2 variants' role in vivo, we used the C. elegans model, where a single gene, tax-6, encodes CnA/TAX-6 and produces TAX-6a and TAX-6b/c variants with distinct LR2 regions. TAX-6a is the predominant neuronal isoform, while TAX-6b/c are enriched in muscles. We generated isoform-specific deletions, gain-of-function mutations, and phosphosite mutations using CRISPR/Cas9, and selectively up-regulated Calcineurin signaling in neurons and muscles with transgenes. We quantified behavioral parameters modulated by Calcineurin signaling, such as crawling speed and responses to noxious heat, both as constitutive and experience-dependent traits. Our results show distinct, non-redundant functions for TAX-6a and TAX-6b/c isoforms, synergistic actions across neurons and muscles, and suggest the differential involvement of TAX-6 phosphorylation-based regulation across these tissues in the modulation of phenotypic outcomes. Overall, our study underscores the importance of LR2-affecting splice variants in regulating both constitutive and experience-dependent behaviors and suggests that such tissue-specific regulation might be conserved across species.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 9","pages":"e1011884"},"PeriodicalIF":3.7,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12503234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145179812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From paleness to albinism: Contribution of OCA2 exon 10 skipping to hypopigmentation.","authors":"Elina Mercier, David-Alexandre Trégouët, Sébastien Campagne, Vincent Michaud, David J Green, Shahram Mesdaghi, Orane Le Gallais, Orphée Jouannigot-Castano, Daniel J Rigden, Catherine Estay-Ahumada, David Hicks, Panagiotis I Sergouniotis, Benoit Arveiler, Sophie Javerzat","doi":"10.1371/journal.pgen.1011801","DOIUrl":"10.1371/journal.pgen.1011801","url":null,"abstract":"<p><p>Pathogenic variants in the OCA2 gene result in oculocutaneous albinism. In humans and several other mammalian species, OCA2 is transcribed into two coding mRNAs, a major transcript that encodes the full-length protein and a minor transcript that skips in-frame exon 10 and has no identified function. By contrast, rodents and non-mammalian vertebrates only express the major transcript. Several rare variants of human OCA2 have been reported to be pathogenic due to increased exon 10 skipping. To understand the vulnerability of human OCA2 to exon 10 skipping and its impact on pigmentation, we first functionally tested a series of rare missense variants spread across exon 10. We found that each variant significantly influences the skipping ratio either positively or negatively. By combining human and murine sequences in functional assays, we found that the skipping ratio depends on particular exonic and intronic combinations. Next, we focused on the most frequent exonic single nucleotide variant of human OCA2, rs1800404-T (c.1065G > A/p.Ala355=), located in exon 10. We show that this variant significantly promotes exon 10 skipping on its own and exhibits an additive effect in cis to previously identified splicing variants likely contributing to their pathogenicity. Association studies reveal that rs1800404-T is tightly associated with lighter skin and hair pigmentation in a representative European population, as has been observed in other populations around the world. Our structural models of the skipped transcript-derived protein support causality by predicting that it could exert a dominant-negative effect, which is consistent with a dose-dependent hypopigmentation response in both pathological and physiological contexts. Overall, the modulation of OCA2 exon 10 skipping by both benign and pathogenic variants provides a basis for improving the genetic diagnosis of albinism, and paves the way for research into the molecular and evolutionary mechanisms behind human pigmentation diversity.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 9","pages":"e1011801"},"PeriodicalIF":3.7,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12463227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145150632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Individual lipid alterations at the origin of neuronal Ceramide Synthase defects.","authors":"Anna B Ziegler, Cedrik Wesselmann, Konstantin Beckschäfer, Anna-Lena Wulf, Neena Dhiman, Peter Soba, Christoph Thiele, Reinhard Bauer, Gaia Tavosanis","doi":"10.1371/journal.pgen.1011880","DOIUrl":"10.1371/journal.pgen.1011880","url":null,"abstract":"<p><p>The brain is highly susceptible to disturbances in lipid metabolism. Among the rare, genetically-linked epilepsies Progressive Myoclonic Epilepsy Type 8 (PME8), associated with the loss of Ceramide Synthase (CerS) activity, causes epileptic symptoms accompanied by early onset of neurodegenerative traits. The function of CerS is embedded in a complex, conserved metabolic pathway, making it difficult to identify the specific disease-relevant alterations. Here, we show that the expression of an enzymatically inactive cerS allele in Drosophila sensory neurons yielded developmental and early onset dendrite loss. Combining lipidomics and refined genetics with quantitative analysis of neuronal morphology in cerS mutants, we identified which lipids species are dysregulated and how they affect neuronal morphology. In cerS mutants, long and very-long acyl-chain C18-C24-ceramides were missing and necessary for dendrite elaboration. In addition, the substrate of CerS, (dh)S, and its metabolite (dh)S1P, increased. Especially increasing (dh)S1P strongly reduces dendritic complexity in cerS mutant neurons. Finally, we performed in vivo experiments to cell-autonomously rescue the morphological defects of cerS mutant neurons and report that a complete rescue can only be achieved if the toxic CerS substrate is converted to produce specific (C18-C24) ceramides. Thus, despite the complex metabolic alterations, our data provides essential information about the metabolic origin of PME8 and delineates a potential therapeutic avenue.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 9","pages":"e1011880"},"PeriodicalIF":3.7,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145151118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}