Int J Mol Sci. 2024 Dec 24;26(1):33. doi: 10.3390/ijms26010033.

ABSTRACT

DNA gyrase is a bacterial type IIA topoisomerase that can create temporary double-stranded DNA breaks to regulate DNA topology and an archetypical target of antibiotics. The widely used quinolone class of drugs use a water-metal ion bridge in interacting with the GyrA subunit of DNA gyrase. Zoliflodacin sits in the same pocket as quinolones but interacts with the GyrB subunit and also stabilizes lethal double-stranded DNA breaks. Gepotidacin has been observed to sit on the twofold axis of the complex, midway between the two four-base-pair separated DNA-cleavage sites and has been observed to stabilize singe-stranded DNA breaks. Here, we use information from three crystal structures of complexes of Staphlococcus aureus DNA gyrase (one with a precursor of gepotidacin and one with the progenitor of zoliflodacin) to propose a simple single moving metal-ion-catalyzed DNA-cleavage mechanism. Our model explains why the catalytic tyrosine is in the tyrosinate (negatively charged) form for DNA cleavage. Movement of a single catalytic metal-ion (Mg2+ or Mn2+) guides water-mediated protonation and cleavage of the scissile phosphate, which is then accepted by the catalytic tyrosinate. Type IIA topoisomerases need to be able to rapidly cut the DNA when it becomes positively supercoiled (in front of replication forks and transcription bubbles) and we propose that the original purpose of the small Greek Key domain, common to all type IIA topoisomerases, was to allow access of the catalytic metal to the DNA-cleavage site. Although the proposed mechanism is consistent with published data, it is not proven and other mechanisms have been proposed. Finally, how such mechanisms can be experimentally distinguished is considered.

PMID:39795899 | DOI:10.3390/ijms26010033

Molecules. 2024 Dec 26;30(1):43. doi: 10.3390/molecules30010043.

ABSTRACT

Curcumin is among the most well-studied natural substances, known for its biological actions within the central nervous system, its antioxidant and anti-inflammatory properties, and human health benefits. However, challenges persist in effectively utilising curcumin, addressing its metabolism and passage through the blood-brain barrier (BBB) in therapies targeting cerebrovascular diseases. Current challenges in curcumin's applications revolve around its effects within neoplastic tissues alongside the development of intelligent formulations to enhance its bioavailability. Formulations have been discovered including curcumin's complexes with brain-derived phospholipids and proteins, or its liposomal encapsulation. These novel strategies aim to improve curcumin's bioavailability and stability, and its capability to cross the BBB, thereby potentially enhancing its efficacy in treating cerebrovascular diseases. In summary, this review provides a comprehensive overview of molecular pathways involved in interactions of curcumin and its metabolites, and brain vascular homeostasis. This review explores cellular and molecular current aspects, of curcumin-based effects with an emphasis on curcumin's metabolism and its impact on pathological conditions, such as neurodegenerative diseases, schizophrenia, and cerebral angiopathy. It also highlights the limitations posed by curcumin's poor bioavailability and discusses ongoing efforts to surpass these impediments to harness the full therapeutic potential of curcumin in neurological disorders.

PMID:39795101 | DOI:10.3390/molecules30010043

Microb Cell Fact. 2025 Jan 10;24(1):14. doi: 10.1186/s12934-024-02641-5.

ABSTRACT

Genome mining is a promising avenue for expanding the repertoire of microbial natural products, which are important for drug development. This approach involves predicting genetically encoded small molecules by examining bacterial genomes via accumulated knowledge of microbial biosynthesis. However, it is also important that the microbes produce the predicted molecule in practice. Here, we introduce an endophytic Streptomyces sp. N50, which was isolated from the medicinal plant Selaginella tamariscina. Upon sequencing its entire genome, 33 biosynthetic gene clusters (BGCs) were identified in a chromosome and a megaplasmid. Subsequent genome mining revealed that the new 15-deoxynaphthomycin could be produced due to the presence of an enoyl reductase domain, which is absent in the known BGC of naphthomycin, a type of ansamycin antibiotics. In addition, the engineered strain with the introduction of the global regulatory gene afsR2 into N50 successfully produced 15-deoxynaphthomycins. Furthermore, molecular network analysis via MS/MS selectively confirmed the presence of additional sulfur-containing 15-deoxynaphthomycin congeners. Eventually, six new 15-deoxynaphthomycins were isolated and elucidated from the engineered strain N50. This family of compounds is known to exhibit various biological activities. Also, the presence of quinone moieties in these compounds, which are known to activate NRF2, they were tested for their ability to activate NRF2. Among the new compounds, three (1, 5, and 6) activated the antioxidant NRF2-ARE signaling pathway. Treatment with these compounds significantly elevated NRF2 levels in HepG2 cells and further induced the expression of NRF2 target genes associated with the antioxidant response. This study suggests that the combination of genome mining, gene engineering and molecular networking is helpful for generating new small molecules as pharmaceutical candidates from microorganisms.

PMID:39794808 | DOI:10.1186/s12934-024-02641-5

BMC Genomics. 2025 Jan 10;26(1):28. doi: 10.1186/s12864-025-11210-y.

ABSTRACT

BACKGROUND: Sugarcane is a crucial crop for both sugar and bioethanol production. The nobilization breeding and utilization of wild germplasm have significantly enhanced its productivity. However, the pollen sterility in Saccharum officinarum restricts its role to being a female parent in crosses with Saccharum spontaneum during nobilization breeding, resulting in a narrow genetic basis for modern sugarcane cultivars. Mitochondria, often referred to as the intracellular "energy factories", provide energy for plant life activities, and are also implicated in cytoplasmic male sterility (CMS).

RESULTS: We performed mitochondrial genome assembly and structural analysis of two Saccharum founding species. We discovered that the proportions of repeat sequences are the primary factor contributing to the variations in mitochondrial genome structure and size between the two Saccharum species. Heterologous expression of the mitochondrial chimeric gene ORF113, which is highly expressed in male-sterile S. officinarum flowers, significantly inhibits growth and ATP synthesis in yeast cells, making it a key candidate CMS-related gene in sugarcane. Furthermore, we developed two co-dominant simple sequence repeat (SSR) markers based on the mitochondrial genome, which can effectively distinguish the cytoplasmic types of the two Saccharum species.

CONCLUSION: In this study, we identified structural variants and developed SSR molecular markers in the mitochondrial genomes of both S. officinarum and S. spontaneum. We also identified a novel mitochondrial chimeric ORF as a key candidate CMS-related gene. These findings offer valuable insights into variety identification, genetic resource development, and cross-breeding strategies in sugarcane.

PMID:39794692 | DOI:10.1186/s12864-025-11210-y

Commun Biol. 2025 Jan 10;8(1):38. doi: 10.1038/s42003-024-07444-3.

ABSTRACT

Prenatal maternal stress (PNMS) determines lifetime mental and physical health. Here, we show in rats that PNMS has consequences for placental function and fetal brain development across four generations (F0-F3). Using a systems biology approach, comprehensive DNA methylation (DNAm), miRNA, and mRNA profiling revealed a moderate impact of PNMS in the F1 generation, but drastic changes in F2 and F3 generations, suggesting compounding effects of PNMS with each successive generation. Both maternal and placental miRNA gene targets included de novo DNA methyltransferases, indicating robust PNMS-induced disruption in the complex epigenetic regulatory network between miRNAs and DNAm. Transgenerational programming mainly involved genes and biological pathways associated with neurological and psychiatric diseases which were linked to maternal-fetal crosstalk facilitated by the placenta. The highly correlated placenta-brain profiles support the use of placenta as a noninvasive biomarker resource to predict pathological changes in the neonatal brain. The transgenerational persistence of critical DNAm, miRNA and mRNA signatures may explain familial non-genetic disease risks.

PMID:39794497 | DOI:10.1038/s42003-024-07444-3

Cell Death Discov. 2025 Jan 10;11(1):2. doi: 10.1038/s41420-025-02286-2.

ABSTRACT

Oral cavity squamous cell carcinoma (OSCC) represents the most prevalent malignancy among head and neck squamous cell carcinomas (HNSCCs). Standard treatment modalities include surgical resection combined with radiation and chemotherapy. However, locoregional failure remains a critical issue affecting the prognosis of OSCC patients, largely due to tumor resistance against radiation or chemotherapy. In this study, we established a gene database related to OSCC recurrence and identified PSMA2 as a novel molecule influencing prognosis in OSCC patients. An independent Taiwanese cohort confirmed that elevated PSMA2 transcript levels were associated with poorer prognosis and contributed to the chemo- and radioresistance phenotype in OSCC. Furthermore, we confirmed that PSMA2 regulates cell cycle, mitochondrial dysfunction, and mitophagy, thereby contributing to carcinogenesis and resistance. Notably, mitophagy inducer exhibit antitumor effects in PSMA2-overexpressing OSCC xenograft mouse model. Collectively, our results provide a mechanistic understanding of the atypical function of PSMA2 in promoting OSCC recurrence.

PMID:39794329 | DOI:10.1038/s41420-025-02286-2

Trends Cancer. 2025 Jan 9:S2405-8033(24)00288-7. doi: 10.1016/j.trecan.2024.12.003. Online ahead of print.

ABSTRACT

Myeloid cells play a crucial dual role in cancer progression and response to therapy, promoting tumor growth, enabling immune suppression, and contributing to metastatic spread. The ability of these cells to modulate the immune system has made them attractive targets for therapeutic strategies aimed at shifting their function from tumor promotion to fostering antitumor immunity. Therapeutic approaches targeting myeloid cells focus on modifying their numbers, genetics, metabolism, and interactions within the tumor microenvironment. These strategies aim to reverse their suppressive functions and redirect them to support antitumor immune responses by inhibiting immunosuppressive pathways, targeting specific receptors, and promoting their differentiation into less immunosuppressive phenotypes. Here, we discuss recent approaches to clinically target tumor myeloid cells, focusing on reprogramming myeloid cells to promote antitumor immunity.

PMID:39794212 | DOI:10.1016/j.trecan.2024.12.003

Curr Biol. 2025 Jan 4:S0960-9822(24)01587-2. doi: 10.1016/j.cub.2024.11.046. Online ahead of print.

ABSTRACT

Anaphase is tightly controlled spatiotemporally to ensure proper separation of chromosomes.1,2,3 The mitotic spindle, the self-organized microtubule structure driving chromosome segregation, scales in size with the available cytoplasm.4,5,6,7 Yet, the relationship between spindle size and chromosome movement remains poorly understood. Here, we address this relationship during the cleavage divisions of the Drosophila blastoderm. We show that the speed of chromosome separation gradually decreases during the four nuclear divisions of the blastoderm. This reduction in speed is accompanied by a similar reduction in spindle length, ensuring that these two quantities are tightly linked. Using a combination of genetic and quantitative imaging approaches, we find that two processes contribute to controlling the speed at which chromosomes move in anaphase: the activity of molecular motors important for microtubule depolymerization and sliding and the cell cycle oscillator. Specifically, we found that the levels of multiple kinesin-like proteins important for microtubule depolymerization, as well as kinesin-5, contribute to setting the speed of chromosome separation. This observation is further supported by the scaling of poleward flux rate with the length of the spindle. Perturbations of the cell cycle oscillator using heterozygous mutants of mitotic kinases and phosphatases revealed that the duration of anaphase increases during the blastoderm cycles and is the major regulator of chromosome velocity. Thus, our work suggests a link between the biochemical rate of mitotic exit and the forces exerted by the spindle. Collectively, we propose that the cell cycle oscillator and spindle length set the speed of chromosome separation in anaphase.

PMID:39793565 | DOI:10.1016/j.cub.2024.11.046

Proc Natl Acad Sci U S A. 2025 Jan 7;122(1):e2413191121. doi: 10.1073/pnas.2413191121. Epub 2024 Dec 30.

ABSTRACT

In species with genetic sex determination (GSD), the sex identity of the soma determines germ cell fate. For example, in mice, XY germ cells that enter an ovary differentiate as oogonia, whereas XX germ cells that enter a testis initiate differentiation as spermatogonia. However, numerous species lack a GSD system and instead display temperature-dependent sex determination (TSD). In the red-eared slider turtle, Trachemys scripta, a TSD model species with a warm female promoting temperature (FPT) and cool male promoting temperature (MPT) system, temperature directly affects germ cell number. In this study, we examined whether temperature directly affects other aspects of germ cell differentiation/sex identity. We uncoupled temperature and the sexual fate of the gonad by incubating eggs at MPT and treating with 17β-estradiol, a scheme that invariably produces ovaries. Through analysis of meiotic spreads, we showed that germ cells in FPT ovaries follow the typical pattern of initiating meiosis and progress through prophase I. However, in E2-induced ovaries that incubated at MPT, germ cells entered prophase I yet fail to exhibit synapsis. These results, combined with our single-cell transcriptome analysis, reveal a direct effect of temperature on germ cell sexual differentiation independent of its effect on the gonadal soma. These results imply that not all events of meiosis are under somatic control, at least not in this TSD species.

PMID:39793067 | DOI:10.1073/pnas.2413191121

Proc Natl Acad Sci U S A. 2025 Jan 7;122(1):e2417941121. doi: 10.1073/pnas.2417941121. Epub 2024 Dec 30.

ABSTRACT

Neurotransmitter release is triggered in microseconds by Ca2+-binding to the Synaptotagmin-1 C2-domains and by SNARE complexes that form four-helix bundles between synaptic vesicles and plasma membranes, but the coupling mechanism between Ca2+-sensing and membrane fusion is unknown. Release requires extension of SNARE helices into juxtamembrane linkers that precede transmembrane regions (linker zippering) and binding of the Synaptotagmin-1 C2B domain to SNARE complexes through a "primary interface" comprising two regions (I and II). The Synaptotagmin-1 Ca2+-binding loops were believed to accelerate membrane fusion by inducing membrane curvature, perturbing lipid bilayers, or helping bridge the membranes, but SNARE complex binding through the primary interface orients the Ca2+-binding loops away from the fusion site, hindering these putative activities. To clarify this paradox, we have used NMR and fluorescence spectroscopy. NMR experiments reveal that binding of C2B domain arginines to SNARE acidic residues at region II remains after disruption of region I, and that a mutation that impairs spontaneous and Ca2+-triggered neurotransmitter release enhances binding through region I. Moreover, fluorescence assays show that Ca2+ does not induce dissociation of Synaptotagmin-1 from membrane-anchored SNARE complex but causes reorientation of the C2B domain. Based on these results and electrophysiological data described by Toulme et al. (https://doi.org/10.1073/pnas.2409636121), we propose that upon Ca2+ binding the Synaptotagmin-1 C2B domain reorients on the membrane and dissociates from the SNAREs at region I but not region II, acting remotely as a lever that pulls the SNARE complex and facilitates linker zippering or other SNARE structural changes required for fast membrane fusion.

PMID:39793049 | DOI:10.1073/pnas.2417941121

Sci Immunol. 2025 Jan 10;10(103):eadq1697. doi: 10.1126/sciimmunol.adq1697. Epub 2025 Jan 10.

ABSTRACT

Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of RAG-mutated patients, we aimed at characterizing the immunopathology associated with each phenotype. Although defective T and B cell development is common to all phenotypes, patients with hypomorphic RAG variants can generate T and B cells with signatures of immune dysregulation and produce autoantibodies to a broad range of self-antigens, including type I interferons. T helper 2 (TH2) cell skewing and a prominent inflammatory signature characterize Omenn syndrome, whereas more hypomorphic forms of RAG deficiency are associated with a type 1 immune profile both in blood and tissues. We used cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) analysis to define the cell lineage-specific contribution to the immunopathology of the distinct RAG phenotypes. These insights may help improve the diagnosis and clinical management of the various forms of the disease.

PMID:39792639 | DOI:10.1126/sciimmunol.adq1697

Cells. 2025 Jan 6;14(1):56. doi: 10.3390/cells14010056.

ABSTRACT

In neurons, the acquisition of a polarized morphology is achieved upon the outgrowth of a single axon from one of several neurites. Small extracellular vesicles (sEVs), such as exosomes, from diverse sources are known to promote neurite outgrowth and thus may have therapeutic potential. However, the effect of fibroblast-derived exosomes on axon elongation in neurons of the central nervous system under growth-permissive conditions remains unclear. Here, we show that fibroblast-derived sEVs promote axon outgrowth and a polarized neuronal morphology in mouse primary embryonic cortical neurons. Mechanistically, we demonstrate that the sEV-induced increase in axon outgrowth requires endogenous Wnts and core PCP components including Prickle, Vangl, Frizzled, and Dishevelled. We demonstrate that sEVs are internalized by neurons, colocalize with Wnt7b, and induce relocalization of Vangl2 to the distal axon during axon outgrowth. In contrast, sEVs derived from neurons or astrocytes do not promote axon outgrowth, while sEVs from activated astrocytes inhibit elongation. Thus, our data reveal that fibroblast-derived sEVs promote axon elongation through the Wnt-PCP pathway in a manner that is dependent on endogenous Wnts.

PMID:39791757 | DOI:10.3390/cells14010056

Elife. 2025 Jan 10;14:e75393. doi: 10.7554/eLife.75393. Online ahead of print.

ABSTRACT

Proliferating animal cells maintain a stable size distribution over generations despite fluctuations in cell growth and division size. Previously, we showed that cell size control involves both cell size checkpoints, which delay cell cycle progression in small cells, and size-dependent regulation of mass accumulation rates (Ginzberg et al., 2018). While we previously identified the p38 MAPK pathway as a key regulator of the mammalian cell size checkpoint (S. Liu et al., 2018), the mechanism of size-dependent growth rate regulation has remained elusive. Here, we quantified global rates of protein synthesis and degradation in cells of varying sizes, both under unperturbed conditions and in response to perturbations that trigger size-dependent compensatory growth slowdown. We found that protein synthesis rates scale proportionally with cell size across cell cycle stages and experimental conditions. In contrast, oversized cells that undergo compensatory growth slowdown exhibit a superlinear increase in proteasome-mediated protein degradation, with accelerated protein turnover per unit mass, suggesting activation of the proteasomal degradation pathway. Both nascent and long-lived proteins contribute to the elevated protein degradation during compensatory growth slowdown, with long-lived proteins playing a crucial role at the G1/S transition. Notably, large G1/S cells exhibit particularly high efficiency in protein degradation, surpassing that of similarly sized or larger cells in S and G2, coinciding with the timing of the most stringent size control in animal cells. These results collectively suggest that oversized cells reduce their growth efficiency by activating global proteasome-mediated protein degradation to promote cell size homeostasis.

PMID:39791360 | DOI:10.7554/eLife.75393

Plant Direct. 2025 Jan 8;9(1):e70035. doi: 10.1002/pld3.70035. eCollection 2025 Jan.

ABSTRACT

Abscission is a tightly regulated process in which plants shed unnecessary, infected, damaged, or aging organs, as well as ripe fruits, through predetermined abscission zones in response to developmental, hormonal, and environmental signals. Despite its importance, the underlying mechanisms remain incompletely understood. This study highlights the deleterious effects of abscission on chloroplast ultrastructure in the cells of the tomato flower pedicel abscission zone, revealing spatiotemporal differential gene expression and key transcriptional networks involved in chloroplast vesiculation during abscission. Significant changes in chloroplast structure and vesicle formation were observed 8 and 14 h after abscission induction, coinciding with the differential expression of vesiculation-related genes, particularly with upregulation of Senescence-Associated Gene 12 (SAG12) and Chloroplast Vesiculation (CV). This suggests a possible vesicle transport of chloroplast degrading material for recycling by autophagy-independent senescence-associated vacuoles (SAVs) and CV-containing vesicles (CCVs). Ethylene signaling appears to be involved in the regulation of these processes, as treatment with a competitive inhibitor of ethylene action, 1-methylcyclopropene, delayed vesiculation, reduced the expression of SAG12, and increased expression of Curvature Thylakoid 1A (CURT1A). In addition, chloroplast vesiculation during abscission was associated with differential expression of photosynthesis-related genes, particularly those involved in light reactions, underscoring the possible functional impact of the observed structural changes. This work provides new insights into the molecular and ultrastructural mechanisms underlying abscission and offers potential new targets for agricultural or biotechnological applications.

PMID:39790709 | PMC:PMC11710935 | DOI:10.1002/pld3.70035

iScience. 2024 Dec 2;28(1):111510. doi: 10.1016/j.isci.2024.111510. eCollection 2025 Jan 17.

ABSTRACT

Chromothripsis, a hallmark of cancer, is characterized by extensive and localized DNA rearrangements involving one or a few chromosomes. However, its genome-wide frequency and characteristics in urothelial carcinoma (UC) remain largely unknown. Here, by analyzing single-regional and multi-regional whole-genome sequencing (WGS), we present the chromothripsis blueprint in 488 UC patients. Chromothripsis events exhibit significant intertumoral heterogeneity, being detected in 41% of UC patients, with an increase from 30% in non-muscle-invasive disease (Ta/1) to 53% in muscle-invasive disease (T2-4). The presence of chromothripsis correlates with an unstable cancer genome and poor clinical outcomes. Analysis of multi-regional WGS data from 52 patients revealed pronounced intratumoral heterogeneity with chromothripsis events detectable only in specific tumor regions rather than uniformly across all areas. Chromothripsis events evolve under positive selection and contribute to tumor dissemination. This study presents a comprehensive genome-wide chromothripsis landscape in UC, highlighting the significance of chromothripsis in UC development.

PMID:39790556 | PMC:PMC11714673 | DOI:10.1016/j.isci.2024.111510

Microlife. 2024 Dec 5;6:uqae024. doi: 10.1093/femsml/uqae024. eCollection 2025.

ABSTRACT

The polyene antimycotic amphotericin B (AmB) and its liposomal formulation AmBisome belong to the treatment options of invasive aspergillosis caused by Aspergillus fumigatus. Increasing resistance to AmB in clinical isolates of Aspergillus species is a growing concern, but mechanisms of AmB resistance remain unclear. In this study, we conducted a proteomic analysis of A. fumigatus exposed to sublethal concentrations of AmB and AmBisome. Both antifungals induced significantly increased levels of proteins involved in aromatic acid metabolism, transmembrane transport, and secondary metabolite biosynthesis. One of the most upregulated proteins was RtaA, a member of the RTA-like protein family, which includes conserved fungal membrane proteins with putative functions as transporters or translocases. Accordingly, we found that RtaA is mainly located in the cytoplasmic membrane and to a minor extent in vacuolar-like structures. Deletion of rtaA led to increased polyene sensitivity and its overexpression resulted in modest resistance. Interestingly, rtaA expression was only induced by exposure to the polyenes AmB and nystatin, but not by itraconazole and caspofungin. Orthologues of rtaA were also induced by AmB exposure in A. lentulus and A. terreus. Deletion of rtaA did not significantly change the ergosterol content of A. fumigatus, but decreased fluorescence intensity of the sterol-binding stain filipin. This suggests that RtaA is involved in sterol and lipid trafficking, possibly by transporting the target ergosterol to or from lipid droplets. These findings reveal the contribution of RtaA to polyene resistance in A. fumigatus, and thus provide a new putative target for antifungal drug development.

PMID:39790482 | PMC:PMC11707875 | DOI:10.1093/femsml/uqae024

Nature. 2025 Jan 9. doi: 10.1038/s41586-024-08560-0. Online ahead of print.

NO ABSTRACT

PMID:39789339 | DOI:10.1038/s41586-024-08560-0

Nat Cell Biol. 2025 Jan 9. doi: 10.1038/s41556-024-01595-5. Online ahead of print.

ABSTRACT

The nuclear matrix, a proteinaceous gel composed of proteins and RNA, is an important nuclear structure that supports chromatin architecture, but its role in human pluripotent stem cells (hPSCs) has not been described. Here we show that by disrupting heterogeneous nuclear ribonucleoprotein U (HNRNPU) or the nuclear matrix protein, Matrin-3, primed hPSCs adopted features of the naive pluripotent state, including morphology and upregulation of naive-specific marker genes. We demonstrate that HNRNPU depletion leads to increased chromatin accessibility, reduced DNA contacts and increased nuclear size. Mechanistically, HNRNPU acts as a transcriptional co-factor that anchors promoters of primed-specific genes to the nuclear matrix with POLII to promote their expression and their RNA stability. Overall, HNRNPU promotes cell-type stability and when reduced promotes conversion to earlier embryonic states.

PMID:39789220 | DOI:10.1038/s41556-024-01595-5

Nat Cancer. 2025 Jan 9. doi: 10.1038/s43018-024-00846-6. Online ahead of print.

NO ABSTRACT

PMID:39789180 | DOI:10.1038/s43018-024-00846-6

Sci Rep. 2025 Jan 9;15(1):1412. doi: 10.1038/s41598-025-85580-4.

ABSTRACT

Rare diseases may affect the quality of life of patients and be life-threatening. Therapeutic opportunities are often limited, in part because of the lack of understanding of the molecular mechanisms underlying these diseases. This can be ascribed to the low prevalence of rare diseases and therefore the lower sample sizes available for research. A way to overcome this is to integrate experimental rare disease data with prior knowledge using network-based methods. Taking this one step further, we hypothesized that combining and analyzing the results from multiple network-based methods could provide data-driven hypotheses of pathogenic mechanisms from multiple perspectives.We analyzed a Huntington's disease transcriptomics dataset using six network-based methods in a collaborative way. These methods either inherently reported enriched annotation terms or their results were fed into enrichment analyses. The resulting significantly enriched Reactome pathways were then summarized using the ontological hierarchy which allowed the integration and interpretation of outputs from multiple methods. Among the resulting enriched pathways, there are pathways that have been shown previously to be involved in Huntington's disease and pathways whose direct contribution to disease pathogenesis remains unclear and requires further investigation.In summary, our study shows that collaborative network analysis approaches are well-suited to study rare diseases, as they provide hypotheses for pathogenic mechanisms from multiple perspectives. Applying different methods to the same case study can uncover different disease mechanisms that would not be apparent with the application of a single method.

PMID:39789061 | DOI:10.1038/s41598-025-85580-4