Disease Models & Mechanisms最新文献

Heart failure with preserved ejection fraction (HFpEF) is a lethal, heterogeneous, geriatric syndrome. Long noncoding RNAs (lncRNAs) constitute the majority of the functional mammalian transcriptome and are key regulators in complex pathophysiological processes. However, the roles of lncRNAs in aging HFpEF associated with thyroid hormone (TH) dysfunction are unclear. We used the well-established ZSF1 rat model to investigate early and severe age-related HFpEF in 5-, 13- or 20-months-old (mo) animals. Both serum THs significantly decreased in HFpEF in a temporal manner. Echocardiograms showed preserved cardiac function. Gravimetric and histologic analyses showed significant cardiac hypertrophy in HFpEF. Microarrays and RT-qPCR revealed that three lncRNAs were significantly increased predominantly in 13-mo HFpEF. Knockdown of lncRNA showed improvement in cell viability, which was further enhanced with T3 (active TH). Microarray analyses showed that two mRNAs were significantly altered in early HFpEF. We also identified previously unreported tissue and serum inflammatory cytokine markers in early and late HFpEF. Taken together, we have shown novel noncoding and coding markers in early- and/or late-aging-related hypothyroid HFpEF. Further studies may develop translatable diagnostic and therapeutic targets for HFpEF.

Heterozygous mutations in the X-linked RNA helicase DDX3X cause DDX3X syndrome, a rare neurodevelopmental disorder associated with cortical malformations and autism spectrum disorder. Among ∼200 known DDX3X variants, half are missense, while the remainder are predicted loss-of-function (LoF) variants. LoF mouse models reveal that Ddx3x controls progenitors' ability to generate excitatory neurons. Yet, how missense mutations impact corticogenesis in vivo is unknown. Here, we generated a conditional mouse model of DDX3XT532M, a clinically severe and recurrent DDX3X syndrome variant found in affected females. Using Emx1-Cre-mediated expression of Ddx3xT532M in cortical progenitors, we showed that Ddx3xT532M alters corticogenesis. Ddx3xT532M conditional hemizygous males have severe microcephaly and apoptosis. In contrast, Ddx3xT532M conditional heterozygous (cHet) females exhibit mild reductions in cortical size and neurogenesis. Using polysome fractionation of Ddx3xT532M and Ddx3xLoF cHet female cortices, we discovered that Ddx3xT532M affects translation, with Ddx3xT532M cHet females showing qualitative differences from Ddx3xLoF cHet females. Collectively, these findings suggest that although Ddx3xT532M and Ddx3xLoF have similar impacts on corticogenesis in cHet females, they have distinct molecular targets. Our study establishes a new in vivo model for understanding the etiology of DDX3X syndrome.

PLA2G6-associated neurodegeneration (PLAN) is a group of rare genetic disorders characterised by progressive neurodegeneration resulting from mutations in the PLA2G6 gene, encoding a calcium-independent phospholipase enzyme. Here, we have explored the effects of decanoic acid (DA), a medium-chain fatty acid, in the fruit fly Drosophila melanogaster models of PLAN and show that DA treatment significantly extends the lifespan, reduces bang sensitivity and improves resistance to heat shock stress. Transcriptional analysis showed that DA affects genes in key signalling pathways, including Insulin/Insulin-like Growth Factor, mTOR, heat shock response, Sirtuin, autophagy and mitochondrial function. Additionally, DA treatment alters the metabolite profiles in PLAN model flies, with the most pronounced changes observed in gut tissue. Pathway analysis of these metabolomic shifts highlights potential therapeutic effects of DA in several pathways, including ATP-binding cassette (ABC) transporters, purine metabolism, cAMP signalling and neuroactive ligand-receptor interactions. These findings suggest that DA may be a promising therapeutic agent for PLAN, offering insights into the mechanisms of the disease and paving the way for future research on medium-chain fatty acids as potential treatments for neurodegenerative diseases.

Zebrafish (Danio rerio) is a leading vertebrate model that has greatly advanced research across fields such as developmental biology, toxicology, immunology and genetics. The rapid generation of high-throughput datasets fueled by advances in genomics, imaging and artificial intelligence (AI) has expanded the zebrafish as an animal model for human disease research and therapeutic discoveries. However, the absence of globally adopted, standardized data reporting methods within the zebrafish community undermines data usability, interoperability and reproducibility. Inconsistent documentation of experimental parameters - including genes, alleles, developmental stages and imaging details - creates barriers to integrating and comparing results across laboratories and disciplines. Challenges are especially pronounced for reporting developmental stages, imaging metadata and chemical exposure protocols, impeding robust data integration and reuse. Although resources such as the Zebrafish Information Network (ZFIN) and global initiatives such as the Monarch Initiative promote ontology-driven data standards, widespread implementation remains limited owing to gaps in community awareness and engagement. The use of species-specific and integrative ontologies is essential for unambiguous data annotation and reliable cross-species comparison, particularly in the context of accelerating AI-driven research. In this Editorial, we summarize current standards relevant to the zebrafish field and highlight the urgent need for collective action. Broad community participation in developing, refining and consistently adopting robust data standards will enhance reproducibility, facilitate interdisciplinary collaboration and ensure that zebrafish research remains a pillar for future scientific and AI-powered advances.

Polymorphisms in the ARMS2/HTRA1 locus on chromosome 10 enhance the risk of geographic atrophy and macular neovascularization, the advanced forms of age-related macular degeneration (AMD). Although HTRA1 mutations have been associated with microvascular defects in the brain, it remains unclear whether changes in HTRA1 expression contribute to AMD pathophysiology. In this study, we showed that, in AMD donor eyes, HTRA1 protein accumulated around the retinal pigment epithelium (RPE)/photoreceptor lesions. We then demonstrated that overexpression of catalytically active, but not catalytically inactive, HTRA1 in RPE cells in mice induced age-dependent loss of photoreceptors, inflammation and a decline in photoreceptor functional responses. This retinal degeneration was not exacerbated when the mice were exposed to phototoxic stress in the constant light exposure preclinical model. However, mice overexpressing catalytically active HTRA1 had significant exacerbation of laser-induced choroidal neovascularization lesions. Finally, as substrate processing may define the molecular basis for HTRA1-induced retinal degeneration, we initiated a proteomics approach and identified the visual cycle key player RBP3 as a disease-relevant HTRA1 substrate in the retina.

Becker muscular dystrophy (BMD) is a rare X-linked recessive neuromuscular disorder, frequently caused by in-frame deletions in the DMD gene that result in the production of a truncated, yet functional, dystrophin protein. The consequences of BMD-causing in-frame deletions on the organism are difficult to predict, especially in regard to long-term prognosis. Here, we used CRISPR-Cas9 to generate a new Dmd Δ52-55 mouse model by deleting exons 52-55 in the Dmd gene, resulting in a BMD-like in-frame deletion. To delineate the long-term effects of this deletion, we studied these mice over 52 weeks by performing histology and echocardiography analyses and assessing motor functions. Our results suggest that truncated dystrophin is sufficient to maintain wildtype-like muscle and heart histology and functions in young mice. However, the truncated protein appeared to be insufficient to maintain normal muscle homeostasis and protect against exercise-induced damage at 52 weeks. To further delineate the effects of this exon 52-55 in-frame deletion, we performed RNA sequencing pre- and post-exercise and identified several differentially expressed pathways that reflect the abnormal muscle phenotype observed at 52 weeks in the BMD model.

Intracerebral haemorrhage (ICH) is a devastating stroke subtype lacking effective therapies. Understanding key pathological processes related to acute brain damage will help deliver better outcomes for ICH. Herein, we provide evidence that myeloid cell trafficking to the parenchyma is a conserved feature of ICH in clinical and experimental settings. Consistent with others, we show that monocytes contribute to acute brain damage following collagenase-induced murine ICH. Using RNA sequencing, we identified the pro-inflammatory cytokine interleukin-1 (IL-1) as a potential upstream regulator of the acute inflammatory response, with histological data pinpointing mononuclear phagocytes as the principal cellular source of IL-1 in patient and animal tissue. In agreement, inhibition of IL-1 receptor 1 (IL-1R1) with IL-1 receptor antagonist reduced recruitment of myeloid cells. However, IL-1R1 inhibition also worsened neuromotor outcomes and reduced cerebral blood flow to the affected hemisphere. Thus, we reveal dichotomous actions of IL-1-dependent inflammation following brain haemorrhage. Although IL-1 regulates myeloid cell trafficking, it also appears to regulate cerebral blood flow. Therefore, further investigation into the consequences of IL-1 signalling following brain haemorrhage is required to clarify future therapeutic options.

Dominant variants in inosine monophosphate dehydrogenase 1 (IMPDH1), a key enzyme in the de novo synthesis of purine bases, cause progressive photoreceptor death, leading to blindness. To investigate the cause of degeneration, we generated the first mutant IMPDH1 animal models and expressed mutant forms of impdh1a in zebrafish cone photoreceptors. Unlike cones expressing exogenous normal impdh1a, cones containing impdh1a with the K238E mutation degenerated. Cones expressing impdh1a with the D226N mutation did not show significant cone loss by 2 years. Steady-state and flux metabolomics in zebrafish retinas revealed no differences in glucose shunting to the pentose phosphate pathway, no change in AMP or GMP due to D226N expression, but reduced AMP/IMP and GMP/IMP in K238E-expressing cones. cGMP levels were normal in both mutant retinas. Further, pde6cw59; impdh1asa23234 double mutant cones were not rescued from degeneration. Both K238E and D226N mutant-containing proteins formed abnormally large mislocalized filaments, which could disrupt normal dynamic protein-protein interactions. Our work disproves the model of a hyperactive enzyme leading to elevated cGMP causing cell death and reveals new defects associated with IMPDH1 mutant expression.