Disease Models & Mechanisms最新文献

Per- and polyfluoroalkyl substances (PFAS), also known as 'forever chemicals', are of high concern for human and ecosystem health. PFAS were first synthesised and developed in the late 1930s, and are now commonplace in many everyday objects, such as frying pans, food packaging and cleaning products. Due to their long half-life, these chemicals remain at high concentrations in both the environment and within exposed organisms, where they have toxic effects. Several model and animal models have been developed to help determine the deleterious effects of PFAS, which has led to the identification of multiple pathways and mechanisms that are affected or presumed to be affected. In this Review, we present an overview of PFAS and discuss possible effects on humans and wildlife. We discuss the pros and cons of various vertebrate and invertebrate model systems that have been used to study PFAS. Finally, to further address these chemicals in the future, we discuss different approaches to removing PFAS from the environment.

CALFAN syndrome is a rare genetic disorder affecting the nervous system and liver, with skeletal abnormalities also reported. It is caused by mutations in SCYL1, a gene encoding a ubiquitously expressed protein localized to the secretory pathway. SCYL1 interacts with trafficking components, including ARF GTPases and the COPI vesicle coat complex, and appears to function in retrograde secretory trafficking. Despite this knowledge, the mechanisms that underlie CALFAN pathology remain poorly understood. Here, using fibroblasts obtained from patients diagnosed with CALFAN syndrome and from SCYL1 knockout fibroblasts, we reveal an accumulation of the abundant secretory cargo procollagen type I in the endoplasmic reticulum (ER) upon SCYL1 deficiency. Surprisingly, we failed to observe procollagen-I-trafficking defects in the SCYL1-deficient cells. Nevertheless, ER accumulation of procollagen-I correlated with ER distension and induction of ER stress in the patient fibroblasts, which also underwent increased cell death. The phenotypes were observed at elevated temperatures, mimicking the induction of pathology under febrile conditions in patients with CALFAN syndrome. Our data suggest that ER stress induction is a pathological mechanism in CALFAN syndrome and that targeting this process may represent a therapeutic strategy.

We recently identified a rare complex syndrome with craniofacial malformations caused by truncating variants in fibrosin-like 1 (FBRSL1). To investigate the function of Fbrsl1 in craniofacial development, we used the Xenopus laevis model to study the cranial neural crest (NC). While Fbrsl1 was largely dispensable for NC induction and early migration, its loss of function impaired NC differentiation and cartilage formation. This was accompanied by increased expression of p53 and cleaved caspase-3, as well as by exon skipping in the mdm2 gene, a negative regulator of p53. Fbrsl1 may directly affect splicing of mdm2, as we find that FBRSL1 interacts with the splicing factor SF3B1. Notably, pharmacological inhibition of p53 partially rescued the craniofacial phenotype, suggesting that p53-mediated apoptosis underlies the NC defects caused by loss of Fbrsl1 function.

The bone morphogenetic proteins (BMPs) are secreted peptide ligands of the transforming growth factor beta (TGF-β) family, initially identified for their roles in development and differentiation across animal species. They are now increasingly recognized for their roles in physiology and infectious disease. In the nematode Caenorhabditis elegans, the BMP ligand DBL-1 controls fat metabolism and immune response, in addition to its roles in body size regulation and development. DBL-1 regulates classical aspects of innate immunity, including the induction of anti-microbial peptides. We theorized that BMP-dependent regulation of fat metabolism could also promote resilience against microbial pathogens. We found that exposure to a bacterial pathogen alters total fat stores, lipid droplet dynamics and lipid metabolism gene expression in a BMP-dependent manner. We further showed that fatty acid desaturation plays a major role in survival on a bacterial pathogen, whereas fatty acid β-oxidation plays a more minor role. We conclude that C. elegans mobilizes fatty acid metabolism in response to pathogen exposure to promote survival. Our investigation provides a framework to study potential metabolic interventions that could support therapeutics that are complementary to antibiotic strategies.

Mitochondria are the regulators of energy production and play a vital role in modulating ageing and age-associated diseases. We investigated the role of sirtuins, a well-studied class of longevity-associated proteins (NAD+-dependent histone deacetylases), in mitochondrial biology and Parkinson's disease pathology. In particular, we endeavoured to study the functional implications of the mitochondrial sirtuin sir-2.2 (orthologue of human SIRT4) in regulating neuroprotection in a Caenorhabditis elegans model of ageing. We observed that, upon sir-2.2 knockdown, alpha-synuclein aggregation was increased and expression of the dopamine transporter dat-1 was reduced. Also, the levels of markers of innate immunity, oxidative stress, mitophagy, mitochondrial unfolded protein response and autophagy were decreased, suggesting an important function of sir-2.2 in maintaining mitochondrial homeostasis, regulating protein clearance and ameliorating the disease condition. Because of their crucial role in regulating oxidative stress and mitochondrial quality control, studying mitochondrial sirtuins will provide therapeutic insights into the metabolic regulation of ageing and neurodegeneration.

Here, we report a genetically engineered mouse model expressing a mutant Wdpcp gene that harbors a deletion of two codons encoding D481 and W482 that correspond to N512 and W513 in human WDPCP. Homozygous mutant mice, designated as Wdpcp-Z11, exhibited severe developmental abnormalities, including neural tube defects, craniofacial malformation, anophthalmia and polydactyly. The mutant WDPCP protein was expressed but failed to dock to the apical surface of the cell. Cilia formation and Hh signaling were severely impaired. Structure predictions located these residues at the juncture of two alpha helices in a conserved, but otherwise uncharacterized, region of WDPCP. Their absence was predicted to impair the linker and reduce conformational stability of WDPCP. Rescue experiments demonstrated that restoring both D481 and W482 are required for a phenotypic recovery. Because a variant of W513 (p.Trp513Ser) is associated with Bardet-Beidl syndrome, insight gained into the structure-function relationship may be valuable for understanding WDPCP-associated ciliopathy.

The 2025 Nobel Prize in Physiology or Medicine has been awarded to Mary Brunkow, Fred Ramsdell and Shimon Sakaguchi "for their discoveries concerning peripheral immune tolerance". This award celebrates research into the mechanisms by which the adaptive immune system learns to tolerate self-antigens, preventing horror autotoxicus, or autoimmune disease. The identification of the regulatory T cell, a type of white blood cell with the capacity to impose self-tolerance on immune responses in the peripheral blood and tissues, required a combination of innovative immunology and genetics. The decades-long task of characterising this cell that can shut down autoimmunity finally intersected with the genetic mapping of the gene FOXP3, which underlies a rare autoimmune condition in humans and mice. This fusion of mouse models and patient-based genetic analysis set off an explosion of research into immune regulation, which is still redefining our knowledge of biology and medicine.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with limited therapeutic options. Here, we present a novel sporadic murine model of Nf1 wild-type MPNST, driven by conditional expression of oncogenic BrafV600E and loss of Pten in the glial lineage using the Plp1::CreERT2 driver. This model allows for highly penetrant and rapid tumor induction through spontaneous formation, localized initiation, or cell transplantation. Comparative analysis with Tyr::CreERT2-driven melanoma revealed striking phenotypic divergence despite shared genetic alterations, underscoring the importance of the cell of origin in shaping tumor identity. In this system, MPNST cells show refractory capacities to induce melanocytic trans-differentiation upon melanoma-promoting signaling cues, such as canonical Wnt signaling gain of function or increased of levels of the epigenetic mark H3K27Me3 upon Ezh2 gain of function. Our findings emphasize the significance of lineage context in tumor initiation and provide a foundation for future mechanistic and therapeutic studies.

Genetic defects in AP2M1, which encodes the μ-subunit of the adaptor protein complex 2 (AP-2) essential for clathrin-mediated endocytosis, cause a rare form of developmental and epileptic encephalopathy (DEE). In this study, we modeled AP2M1-DEE in Drosophila melanogaster to gain deeper insights into the underlying disease mechanisms. Pan-neuronal RNA interference against the Drosophila AP2M1 ortholog, AP-2µ, resulted in a consistent heat-sensitive paralysis phenotype and altered morphology in class IV dendritic arborization neurons. Unexpectedly, affected flies were resistant to antiseizure medications and exhibited decreased susceptibility to electrically induced seizures. A CRISPR-engineered fly line carrying the recurrent human disease variant p.Arg170Trp displayed a milder, seizure-resistant phenotype. Although these findings contrast with the human phenotype, they align with previous studies on other clathrin-mediated endocytosis-related genes in Drosophila. Our results suggest that hyperexcitability and seizures in AP2M1-DEE may stem from broader defects in neuronal development rather than direct synaptic dysfunction.

The chronic inflammation observed during type 2 diabetes (T2D) is associated with spinal pathologies, including intervertebral disc (IVD) degeneration and chronic spine pain. Despite confounding factors, such as obesity, studies show that, after adjusting for age, body mass index and genetics (e.g. twins), patients with T2D experience disproportionate severity of IVD degeneration and/or back pain than individuals without T2D. We hypothesized that chronic T2D fosters a proinflammatory microenvironment within the IVD that promotes degeneration and disrupts homeostasis. To test this, we evaluated two common mouse models of T2D - leptin-receptor deficient (db/db) mice and mice with a chronic high-fat diet and impaired β-cell function (STZ-HFD). IVDs of STZ-HFD mice exhibited more severe degeneration and elevated chemokine expression than controls. RNA sequencing further revealed extensive transcriptional dysregulation in STZ-HFD IVDs not observed in db/db IVDs. STZ-HFD IVDs expressed enzymes that enhance advanced glycation end product precursors, impaired non-AGE DAMP pathways and suppressed RAGE turnover. These results suggest that, under controlled genetic and environmental conditions, the STZ-HFD model more accurately reflects the multifactorial inflammatory milieu characteristic of T2D-induced IVD degeneration.