Disease Models & Mechanisms最新文献

Alzheimer's disease is associated with the misfolding and aggregation of two distinct proteins, beta-amyloid and tau. Previously, it has been shown that activation of the cytoprotective heat shock response (HSR) pathway reduces beta-amyloid toxicity. Here, we show that activation of the HSR is also protective against tau toxicity in a cell-autonomous manner. Overexpression of HSF-1, the master regulator of the HSR, ameliorates the motility defect and increases the lifespan of transgenic C. elegans expressing human tau. By contrast, RNA interference of HSF-1 exacerbates the motility defect and shortens lifespan. Targeting regulators of the HSR also affects tau toxicity. Additionally, two small-molecule activators of the HSR, Geranylgeranylacetone (GGA) and Arimoclomol (AC), have substantial beneficial effects. Taken together, this research expands the therapeutic potential of HSR manipulation to tauopathies and reveals that the HSR can impact both beta-amyloid and tau proteotoxicity in Alzheimer's disease.

The microbiome can influence cancer development and progression. However, less is known about the role of the skin microbiota in melanoma. Here, we took advantage of a zebrafish melanoma model to probe the effects of Staphylococcus aureus on melanoma invasion. We found that S. aureus produces factors that enhance melanoma invasion and dissemination in zebrafish larvae. We used a published in vitro 3D cluster formation assay that correlates increased clustering with tumor invasion. S. aureus supernatant increased clustering of melanoma cells and was abrogated by a Rho-Kinase inhibitor, implicating a role for Rho-GTPases. The melanoma clustering response was specific to S. aureus but not to other staphylococcal species, including S. epidermidis. Our findings suggest that S. aureus promotes melanoma clustering and invasion via lipids generated by the lipase Sal2 (officially known as GehB). Taken together, these findings suggest that specific bacterial products mediate melanoma invasive migration in zebrafish.

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 employed CRISPR-Cas9 to generate a new Dmd del52-55 mouse model by deleting exons 52-55, 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 a truncated dystrophin is sufficient to maintain wildtype-like muscle and heart histology and functions in young mice. However, the truncated protein appears insufficient to maintain normal muscle homeostasis and protect against exercise-induced damage at 52 weeks. To further delineate the effects of this exon52-55 in-frame deletion, we performed RNA-Seq pre- and post-exercise and identified several differentially expressed pathways that reflect the abnormal muscle phenotype observed at 52 weeks in the BMD model.

Despite advancements in treatment, approximately 25% of patients with breast cancer experience long-term skeletal muscle wasting (SMW), which limits mobility, reduces drug tolerance and adversely impacts survival. By understanding the underlying molecular mechanisms of SMW, we may be able to develop new strategies to alleviate this condition and improve the lives of patients with breast cancer. Chemokines are small soluble factors that regulate homing of immune cells to tissues during inflammation. In breast cancers, overexpression of C-C chemokine ligand 2 (CCL2) correlates with unfavorable prognosis. Elevated levels of CCL2 in peripheral blood indicate possible systemic effects of this chemokine in patients with breast cancer. Here, we investigated the role of CCL2 signaling on SMW in tumor and non-tumor contexts. In vitro, increasing concentrations of CCL2 inhibited myoblast and myotube function through C-C chemokine receptor 2 (CCR2)-dependent mechanisms involving JNK, SMAD3 and AMPK signaling. In healthy mice, delivery of recombinant CCL2 protein promoted SMW in a dose-dependent manner. In vivo knockdown of breast tumor-derived CCL2 partially protected against SMW. Overall, chronic, upregulated CCL2-CCR2 signaling positively regulates SMW, with implications for therapeutic targeting.

Hypertrophic cardiomyopathy (HCM) is an inherited heart muscle disease that is characterised by left ventricular wall thickening, cardiomyocyte disarray and fibrosis, and is associated with arrhythmias, heart failure and sudden death. However, it is unclear to what extent the electrophysiological disturbances that lead to sudden death occur secondary to structural changes in the myocardium or as a result of HCM cardiomyocyte electrophysiology. In this study, we used an induced pluripotent stem cell model of the R403Q variant in myosin heavy chain 7 (MYH7) to study the electrophysiology of HCM cardiomyocytes in electrically coupled syncytia, revealing significant conduction slowing and increased spatial dispersion of repolarisation - both well-established substrates for arrhythmia. Analysis of rhythmonome protein expression in MYH7 R403Q cardiomyocytes showed reduced expression of connexin-43 (also known as GJA1), sodium channels and inward rectifier potassium channels - a three-way hit that reduces electrotonic coupling and slows cardiac conduction. Our data represent a previously unreported, biophysical basis for arrhythmia in HCM that is intrinsic to cardiomyocyte electrophysiology. Later in the progression of the disease, these proarrhythmic phenotypes may be accentuated by myocyte disarray and fibrosis to contribute to sudden death.

The size and composition of the intracellular DNA precursor pool is integral to the maintenance of genome stability, and this relationship is fundamental to our understanding of cancer. Key aspects of carcinogenesis, including elevated mutation rates and induction of certain types of DNA damage in cancer cells, can be linked to disturbances in deoxynucleoside triphosphate (dNTP) pools. Furthermore, our approaches to treat cancer heavily exploit the metabolic interplay between the DNA and the dNTP pool, with a long-standing example being the use of antimetabolite-based cancer therapies, and this strategy continues to show promise with the development of new targeted therapies. In this Review, we compile the current knowledge on both the causes and consequences of dNTP pool perturbations in cancer cells, together with their impact on genome stability. We outline several outstanding questions remaining in the field, such as the role of dNTP catabolism in genome stability and the consequences of dNTP pool expansion. Importantly, we detail how our mechanistic understanding of these processes can be utilised with the aim of providing better informed treatment options to patients with cancer.

A pervasive discussion point within the scientific community is the value of unpublished or unavailable data. Researchers, funders, ethical review bodies, editors and publishers have all highlighted the need to make more data available to enhance experimental planning and interpretation and to prevent others from repeating similar experiments. This is particularly important in the context of experimentation involving animals and efforts towards replacement, refinement and reduction. However, despite this broad agreement, sharing data that show inconclusive, statistically insignificant or unremarkable results is still not common practice. In this Editorial, we will highlight the value of what are often coined negative (or null) data and outline some emerging initiatives to address the gap between data generated in laboratories and data available to the wider scientific community.

N-methyl-D-aspartate (NMDA)-induced retinal damage has been well studied in rodents, but the detailed mechanisms have not yet been characterized in nonhuman primates. Here, we characterized the retinal degenerative effects of NMDA on rhesus monkeys in vivo. NMDA saline or saline-only control was injected intravitreally to the randomly assigned eyes and contralateral eyes of four rhesus monkeys, respectively. The structural and functional changes of retina were characterized by optical coherence tomography and electroretinography on days 0, 4, 30 and 60 post injection. Both optic discs and macular areas of the NMDA-injected eyes initially presented with a transient retinal thickening, followed by continued retinal thinning. The initial, transient retinal thickening has also been observed in glaucoma patients, but this has not been reported in rodent NMDA models. This initial response was followed by loss of retina ganglion cells (RGCs), which is similar to glaucomatous optic neuropathy and other RGC-related retinal degenerations. The amplitudes of both the photopic negative response and pattern electroretinogram decreased significantly and remained low until the end of the study. Thus, the NMDA monkey model may serve as a more clinically relevant animal model of retinal damage.

The salivary glands are often damaged during head and neck cancer radiotherapy. This results in chronic dry mouth, which adversely affects quality of life and for which there is no long-term cure. Mouse models of salivary gland injury are routinely used in regenerative research. However, there is no clear consensus on the radiation regime required to cause injury. Here, we analysed three regimes of γ-irradiation of the submandibular salivary gland. Transcriptional analysis, immunofluorescence and flow cytometry was used to profile DNA damage, gland architecture and immune cell changes 3 days after single doses of 10 or 15 Gy or three doses of 5 Gy. Irrespective of the regime, radiation induced comparable levels of DNA damage, cell cycle arrest, loss of glandular architecture, increased pro-inflammatory cytokines and a reduction in tissue-resident macrophages, relative to those observed in non-irradiated submandibular glands. Given these data, coupled with the fact that repeated anaesthetic can negatively affect animal welfare and interfere with saliva secretion, we conclude that a single dose of 10 Gy irradiation is the most refined method of inducing acute salivary gland injury in a mouse model.