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Mechanical Force of Uterine Occupation Enables Large Vesicle Extrusion From Proteostressed Maternal Neurons
Wang et al., eLife. 2024.
https://pubmed.ncbi.nlm.nih.gov/39255003
This study investigates how mechanical forces from uterine occupation influence large vesicle extrusion (exopher production) from proteostressed maternal neurons in Caenorhabditis elegans. Exophers, previously found to remove damaged cellular components, are poorly understood. Researchers demonstrate that mechanical stress significantly increases exopher release from touch receptor neurons (i.e., ALMR) during peak reproductive periods, coinciding with egg production. Genetic disruptions reducing reproductive activity suppress exopher extrusion, whereas interventions promoting egg retention enhance it. These findings reveal that reproductive and mechanical factors modulate neuronal stress responses, providing insight on how systemic physiological changes affect neuronal health and proteostasis, with broader implications for reproductive-neuronal interactions. Supported by ORIP (R24OD010943, P40OD010440), NIA, and NIGMS.
Proinflammatory Cytokines Suppress Stemness-Related Properties and Expression of Tight Junction in Canine Intestinal Organoids
Nakazawa et al., In Vitro Cellular & Developmental Biology—Animal. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11419940
Cells in the gastrointestinal tract are exposed to numerous stressors that can promote excessive inflammation, including environmental chemicals and dietary substances. Researchers studied how canine intestinal epithelial cell (IEC)–derived organoids responded to exposure to one of three proinflammatory cytokines; interferon-γ (IFN-γ), tumor necrosis factor-α (TNFα), or interleukin-1β (IL1β). Exposure to IFN-γ resulted in downregulation of the stem cell marker Lgr5. Only IFN-γ exposure resulted in increased production of caspase 3 and caspase 8. Exposure to either IFN-γ or IL1β resulted in suppressed cell proliferation. The pro-inflammatory cytokines caused reduced tight junction protein expression and compromised membrane integrity. These findings are important to understanding IEC response to different inflammatory stimuli and to broadening knowledge of gut physiology. Supported by ORIP (K01OD030515, R21OD031903).
Establishment and Characterization of Three Human Ocular Adnexal Sebaceous Carcinoma Cell Lines
Lee et al., International Journal of Molecular Sciences. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11432008
Researchers established three new cell lines to model ocular adnexal sebaceous carcinoma (SebCA) and test new therapies. SebCA is a highly problematic periorbital tumor requiring aggressive surgical treatment, and its pathobiology remains poorly understood. With consent from one male and two female patients, tumor tissue was cultured under conditional reprograming, and the cells were analyzed for growth, clonogenicity, apoptosis, and differentiation using methods including western blotting, short tandem repeat profiling, and next-generation sequencing. These newly developed cell lines provide valuable preclinical models for understanding and treating SebCA. Supported by ORIP (K01OD034451).
The Splicing Factor hnRNPL Demonstrates Conserved Myocardial Regulation Across Species and Is Altered in Heart Failure
Draper et al., FEBS Letters. 2024.
https://pubmed.ncbi.nlm.nih.gov/39300280/
The 5-year mortality rate of heart failure (HF) is approximately 50%. Gene splicing, induced by splice factors, is a post-transcriptional modification of mRNA that may regulate pathological remodeling in HF. Researchers investigated the role of the splice factor heterogenous nuclear ribonucleoprotein-L (hnRNPL) in cardiomyopathy. hnRNPL protein expression is significantly increased in a male C57BL/6 transaortic constriction–induced HF mouse model and in clinical samples derived from canine or human HF patients. Cardiac-restricted knockdown of the hnRNPL homolog in Drosophila revealed systolic dysfunction and reduced life span. This study demonstrates a conserved cross-species role of hnRNPL in regulating heart function. Supported by ORIP (K01OD028205) and NHLBI.
Alterations in Tumor Aggression Following Androgen Receptor Signaling Restoration in Canine Prostate Cancer Cell Lines
Vasilatis et al., International Journal of Molecular Sciences. 2024.
https://pubmed.ncbi.nlm.nih.gov/39201315
Prostate cancer (PCa) ranks second worldwide in cancer-related mortality, but only a few animal models exhibit naturally occurring PCa that recapitulates the symptoms of the disease. Neutered dogs have an increased risk of PCa and often lack androgen receptor (AR) signaling, which is involved in upregulating tumorigenesis but can also suppress aggressive cell growth. In this study, researchers sought to understand more about the role of AR signaling in canine PCa initiation and progression by restoring AR in canine PCa cell lines and treating them with dihydrotestosterone. One cell line exhibited AR-mediated tumor suppression; one cell line showed altered proliferation (but not migration or invasion); and a third cell line exhibited AR-mediated alterations in migration and invasion (but not proliferation). The study highlights the heterogeneous nature of PCa in dogs and humans but suggests that AR signaling might have therapeutic potential under certain conditions. Supported by ORIP (T32OD011147).
Canine RNF170 Single Base Deletion in a Naturally Occurring Model for Human Neuroaxonal Dystrophy
Cook et al., Movement Disorders. 2024.
https://pubmed.ncbi.nlm.nih.gov/39177409/
A newly recognized progressive neurodegenerative disorder in Miniature American Shepherd (MAS) dogs affects gait in young adult dogs and is characterized by pelvic limb weakness and ataxia. The authors of this study used genetic analysis to map the underlying cause of the disorder, a single base-pair deletion in the ring finger protein 170 (RNF170) gene that was predicted to cause early truncation of the RNF170 protein. RNF170 variants previously were identified in human patients with spastic paraplegia-85 (SPG85) who exhibit similar clinical and pathological phenotypes to RNF170-mutant dogs. SPG85 belongs to a group of inherited neurodegenerative disorders collectively referred to as neuroaxonal dystrophy (NAD). The authors of this paper propose that RNF170-mutant MAS dogs serve as a large animal model to study underlying mechanisms and therapeutics for NAD. Supported by ORIP (K01OD027051).
Acquired Dysfunction of CFTR Underlies Cystic Fibrosis-Like Disease of the Canine Gallbladder
Gookin et al., American Journal of Physiology-Gastrointestinal and Liver Physiology. 2024.
https://pubmed.ncbi.nlm.nih.gov/39041675/
Mucocele formation in dogs is pathologically similar to cystic fibrosis. In this study, researchers investigated the role of cystic fibrosis transmembrane conductance regulator (CFTR) in the pathogenesis of the disease. They determined the location and frequency of disease-associated variants in the coding region of CFTR using whole-genome sequence data from 2,642 dogs representing breeds at low risk, high risk, or with confirmed disease. The authors’ findings establish significant loss of CFTR-dependent anion secretion by mucocele gallbladder mucosa. There were no significant differences in CFTR gene variant frequency, type, or predicted impact comparing low-risk, high-risk, and definitively diagnosed groups of dogs. Their results suggest a disease of the canine gallbladder that is similar to cystic fibrosis and is driven by CFTR dysfunction. Supported by ORIP (T35OD011070, K01OD027058).
Cdk8/CDK19 Promotes Mitochondrial Fission Through Drp1 Phosphorylation and Can Phenotypically Suppress Pink1 Deficiency in Drosophila
Liao et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-47623-8
Pink1 is a mitochondrial kinase implicated in Parkinson’s disease and is conserved among humans, rodents, and flies. In this study, researchers found that Cdk8 in Drosophila (i.e., the orthologue of vertebrate CDK8 and CDK19) promotes the phosphorylation of Drp1 (i.e., a protein required for mitochondrial fission) at the same residue as Pink1. Cdk8 is expressed in both the cytoplasm and nucleus, and neuronal loss of Cdk8 reduces fly life span and causes bang sensitivity and elongated mitochondria in both muscles and neurons. Overexpression of Cdk8 suppresses elevated levels of reactive oxygen species, mitochondrial dysmorphology, and behavioral defects in flies with low levels of Pink1. These findings suggest that Cdk8 regulates Drp1-mediated mitochondrial fission in a similar manner as Pink1 and may contribute to the development of Parkinson’s disease. Supported by ORIP (R24OD022005, R24OD031447, P40OD018537, P40OD010949), NICHD, and NINDS.
Identifying Potential Dietary Treatments for Inherited Metabolic Disorders Using Drosophila Nutrigenomics
Martelli et al., Cell Reports. 2024.
https://www.sciencedirect.com/science/article/pii/S221112472400189X?via%3Dihub=
Inherited metabolic disorders are known to cause severe neurological impairment and child mortality and can sometimes respond to dietary treatment; however, a suitable paradigm for testing diets is lacking for developing effective dietary treatment. In this study, researchers found that 26 of 35 Drosophila amino acid disorder models screened for disease–diet interactions displayed diet-altered development and/or survival. Among these models, researchers showed that dietary cysteine depletion normalizes metabolic profile and rescues development, neurophysiology, behavior, and life span in a model for isolated sulfite oxidase deficiency. These findings demonstrate the value of using Drosophila in studying diet-sensitive metabolic disorders and developing potential dietary therapies. Supported by ORIP (R24OD031447) and NHGRI.
De Novo Variants in FRYL Are Associated With Developmental Delay, Intellectual Disability, and Dysmorphic Features
Pan et al., The American Journal of Human Genetics. 2024.
https://www.cell.com/ajhg/fulltext/S0002-9297(24)00039-9
FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans, and its functions in mammals are largely unknown. Investigators report 13 individuals who have de novo heterozygous variants in FRYL and one individual with a heterozygous FRYL variant that is not confirmed to be de novo. The individuals present with developmental delay; intellectual disability; dysmorphic features; and other congenital anomalies in cardiovascular, skeletal, gastrointestinal, renal, and urogenital systems. Using fruit flies, investigators provide evidence that haploinsufficiency in FRYL likely underlies a disorder in humans with developmental and neurological symptoms. Supported by ORIP (U54OD030165), NHLBI, NICHD, and NCATS.