International Journal of Molecular Sciences

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12 pages, 2001 KiB

Open AccessArticle

Monitoring Nrf2/ARE Pathway Activity with a New Zebrafish Reporter System

by Lorenzo Badenetti, Rosa Manzoli, Michela Rubin, Giorgio Cozza and Enrico Moro

Int. J. Mol. Sci. 2023, 24(7), 6804; https://doi.org/10.3390/ijms24076804 - 06 Apr 2023

Cited by 4 | Viewed by 1898

Abstract

Among multiple cytoprotective mechanisms, eukaryotic cells exhibit a complex transcriptional program relying on the Nrf2 transcription factor, which is generally recruited upon biological stressors including oxidative-stress-based cellular insults. The relevance of this master regulator has remarkably emerged in recent years in several research [...] Read more.

Among multiple cytoprotective mechanisms, eukaryotic cells exhibit a complex transcriptional program relying on the Nrf2 transcription factor, which is generally recruited upon biological stressors including oxidative-stress-based cellular insults. The relevance of this master regulator has remarkably emerged in recent years in several research fields such as cancer, inflammatory disorders and age-related neurological diseases. Here, we document the generation and characterization of a novel Nrf2/ARE pathway biosensor fish which exhibits a dynamic spatiotemporal expression profile during the early developmental stages. The transgenic line is responsive to known Nrf2 pathway modulators but also to Edaravone, which direct activity on the Nrf2 pathway has never been documented in a live transgenic fish model. We also show that the reporter is faithfully activated during fin regeneration, and its degree of expression is slightly affected in a glucocerebrosidase (Gba1) morphant zebrafish model. Therefore, this novel transgenic fish may represent a valuable tool to be exploited for the characterization of zebrafish models of human diseases, as well as for primary high-throughput drug screening. Full article

(This article belongs to the Special Issue Zebrafish as a Model in Human Disease)

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21 pages, 3481 KiB

Open AccessArticle

Combined Inhibition of Hedgehog and HDAC6: In Vitro and In Vivo Studies Reveal a New Role for Lysosomal Stress in Reducing Glioblastoma Cell Viability

by Alex Pezzotta, Loredana Brioschi, Sabrina Carbone, Beatrice Mazzoleni, Vittorio Bontempi, Federica Monastra, Laura Mauri, Anna Marozzi, Marina Mione, Anna Pistocchi and Paola Viani

Int. J. Mol. Sci. 2023, 24(6), 5771; https://doi.org/10.3390/ijms24065771 - 17 Mar 2023

Cited by 1 | Viewed by 1869

Abstract

Glioblastoma multiforme (GBM) is the most common and malignant brain tumor in adults. The invasiveness and the rapid progression that characterize GBM negatively impact patients’ survival. Temozolomide (TMZ) is currently considered the first-choice chemotherapeutic agent. Unfortunately, over 50% of patients with GBM do [...] Read more.

Glioblastoma multiforme (GBM) is the most common and malignant brain tumor in adults. The invasiveness and the rapid progression that characterize GBM negatively impact patients’ survival. Temozolomide (TMZ) is currently considered the first-choice chemotherapeutic agent. Unfortunately, over 50% of patients with GBM do not respond to TMZ treatment, and the mutation-prone nature of GBM enables the development of resistance mechanisms. Therefore, efforts have been devoted to the dissection of aberrant pathways involved in GBM insurgence and resistance in order to identify new therapeutic targets. Among them, sphingolipid signaling, Hedgehog (Hh) pathway, and the histone deacetylase 6 (HDAC6) activity are frequently dysregulated and may represent key targets to counteract GBM progression. Given the positive correlation between Hh/HDAC6/sphingolipid metabolism in GBM, we decided to perform a dual pharmacological inhibition of Hh and HDAC6 through cyclopamine and tubastatin A, respectively, in a human GMB cell line and zebrafish embryos. The combined administration of these compounds elicited a more significant reduction of GMB cell viability than did single treatments in vitro and in cells orthotopically transplanted in the zebrafish hindbrain ventricle. We demonstrated, for the first time, that the inhibition of these pathways induces lysosomal stress which results in an impaired fusion of lysosomes with autophagosomes and a block of sphingolipid degradation in GBM cell lines. This condition, which we also recapitulated in zebrafish embryos, suggests an impairment of lysosome-dependent processes involving autophagy and sphingolipid homeostasis and might be instrumental in the reduction of GBM progression. Full article

(This article belongs to the Special Issue Zebrafish as a Model in Human Disease)

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23 pages, 4799 KiB

Open AccessArticle

Expression of the Z Variant of α1-Antitrypsin Suppresses Hepatic Cholesterol Biosynthesis in Transgenic Zebrafish

by Connie Fung, Brendan Wilding, Ralf B. Schittenhelm, Robert J. Bryson-Richardson and Phillip I. Bird

Int. J. Mol. Sci. 2023, 24(3), 2475; https://doi.org/10.3390/ijms24032475 - 27 Jan 2023

Viewed by 1861

Abstract

Individuals homozygous for the Pi*Z allele of SERPINA1 (ZAAT) are susceptible to lung disease due to insufficient α1-antitrypsin secretion into the circulation and may develop liver disease due to compromised protein folding that leads to inclusion body formation in the endoplasmic reticulum (ER) [...] Read more.

Individuals homozygous for the Pi*Z allele of SERPINA1 (ZAAT) are susceptible to lung disease due to insufficient α1-antitrypsin secretion into the circulation and may develop liver disease due to compromised protein folding that leads to inclusion body formation in the endoplasmic reticulum (ER) of hepatocytes. Transgenic zebrafish expressing human ZAAT show no signs of hepatic accumulation despite displaying serum insufficiency, suggesting the defect in ZAAT secretion occurs independently of its tendency to form inclusion bodies. In this study, proteomic, transcriptomic, and biochemical analysis provided evidence of suppressed Srebp2-mediated cholesterol biosynthesis in the liver of ZAAT-expressing zebrafish. To investigate the basis for this perturbation, CRISPR/Cas9 gene editing was used to manipulate ER protein quality control factors. Mutation of erlec1 resulted in a further suppression in the cholesterol biosynthesis pathway, confirming a role for this ER lectin in targeting misfolded ZAAT for ER-associated degradation (ERAD). Mutation of the two ER mannosidase homologs enhanced ZAAT secretion without inducing hepatic accumulation. These insights into hepatic ZAAT processing suggest potential therapeutic targets to improve secretion and alleviate serum insufficiency in this form of the α1-antitrypsin disease. Full article

(This article belongs to the Special Issue Zebrafish as a Model in Human Disease)

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18 pages, 3789 KiB

Open AccessArticle

Deficiency of Adipose Triglyceride Lipase Induces Metabolic Syndrome and Cardiomyopathy in Zebrafish

by Hsin-Hung Lai, Kun-Yun Yeh, Hung-Ming Hsu and Guor Mour Her

Int. J. Mol. Sci. 2023, 24(1), 117; https://doi.org/10.3390/ijms24010117 - 21 Dec 2022

Cited by 3 | Viewed by 2054

Abstract

Lipid metabolism dysfunction is related to clinical disorders including obesity, cancer, liver steatosis, and cardiomyopathy. Impaired lipolytic enzymes result in altered release of free fatty acids. The dramatic change in dyslipidemia is important in lipotoxic cardiomyopathy. Adipose triglyceride lipase (ATGL) catalyzes the lipolysis [...] Read more.

Lipid metabolism dysfunction is related to clinical disorders including obesity, cancer, liver steatosis, and cardiomyopathy. Impaired lipolytic enzymes result in altered release of free fatty acids. The dramatic change in dyslipidemia is important in lipotoxic cardiomyopathy. Adipose triglyceride lipase (ATGL) catalyzes the lipolysis of triacylglycerol to reduce intramyocardial triglyceride levels in the heart and improve myocardial function. We examined the role of ATGL in metabolic cardiomyopathy by developing an Atgl knockout (ALKO) zebrafish model of metabolic cardiomyopathy disease by continuously expressing CRISPR/Cas9 protein and atgl gene guide RNAs (gRNAs). The expressed Cas9 protein bound to four gRNAs targeting the atgl gene locus, facilitating systemic gene KO. Ablation of Atgl interfered with lipid metabolism, which induced hyperlipidemia and hyperglycemia. ALKO adults and embryos displayed hypertrophic hearts. ALKO presented a typical dilated cardiomyopathy profile with a remarkable reduction in four sarcomere genes (myosin heavy chain 7-like, actin alpha cardiac muscle 1b, myosin binding protein C3, and troponin T type 2a) and two Ca²⁺ handling regulator genes (tropomyosin 4b and ATPase sarcoplasmic/endoplasmic reticulum Ca²⁺ transporting 2b). Immune cell infiltration in cardiac tissue of ALKO provided direct evidence of advanced metabolic cardiomyopathy. The presently described model could become a powerful tool to clarify the underlying mechanism between metabolic disorders and cardiomyopathies. Full article

(This article belongs to the Special Issue Zebrafish as a Model in Human Disease)

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15 pages, 5673 KiB

Open AccessArticle

Evaluation of Cisplatin-Induced Pathology in the Larval Zebrafish Lateral Line

by David S. Lee, Angela Schrader, Emily Bell, Mark E. Warchol and Lavinia Sheets

Int. J. Mol. Sci. 2022, 23(22), 14302; https://doi.org/10.3390/ijms232214302 - 18 Nov 2022

Cited by 1 | Viewed by 2104

Abstract

Cisplatin is an effective anticancer agent, but also causes permanent hearing loss by damaging hair cells—the sensory receptors essential for hearing. There is an urgent clinical need to protect cochlear hair cells in patients undergoing cisplatin chemotherapy. The zebrafish lateral line organ contains [...] Read more.

Cisplatin is an effective anticancer agent, but also causes permanent hearing loss by damaging hair cells—the sensory receptors essential for hearing. There is an urgent clinical need to protect cochlear hair cells in patients undergoing cisplatin chemotherapy. The zebrafish lateral line organ contains hair cells and has been frequently used in studies to screen for otoprotective compounds. However, these studies have employed a wide range of cisplatin dosages and exposure times. We therefore performed a comprehensive evaluation of cisplatin ototoxicity in the zebrafish lateral line with the goal of producing a standardized, clinically relevant protocol for future studies. To define the dose- and time-response patterns of cisplatin-induced hair-cell death, we treated 6-day-old larvae for 2 h in 50 µM–1 mM cisplatin and allowed them to recover. We observed delayed hair cell death, which peaked at 4–8 h post-exposure. Cisplatin also activated a robust inflammatory response, as determined by macrophage recruitment and phagocytosis of hair cells. However, selective depletion of macrophages did not affect hair cell loss. We also examined the effect of cisplatin treatment on fish behavior and found that cisplatin-induced lateral line injury measurably impaired rheotaxis. Finally, we examined the function of remaining hair cells that appeared resistant to cisplatin treatment. We observed significantly reduced uptake of the cationic dye FM1-43 in these cells relative to untreated controls, indicating that surviving hair cells may be functionally impaired. Cumulatively, these results indicate that relatively brief exposures to cisplatin can produce hair cell damage and delayed hair cell death. Our observations provide guidance on standardizing methods for the use of the zebrafish model in studies of cisplatin ototoxicity. Full article

(This article belongs to the Special Issue Zebrafish as a Model in Human Disease)

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18 pages, 4077 KiB

Open AccessArticle

Prolonged Hyperglycemia Causes Visual and Cognitive Deficits in Danio rerio

by Elizabeth McCarthy, Jillian Dunn, Kaylee Augustine and Victoria P. Connaughton

Int. J. Mol. Sci. 2022, 23(17), 10167; https://doi.org/10.3390/ijms231710167 - 05 Sep 2022

Viewed by 1406

Abstract

The present study induced prolonged hyperglycemia (a hallmark symptom of Type 2 diabetes [T2DM]) in Danio rerio (zebrafish) for eight or twelve weeks. The goal of this research was to study cognitive decline as well as vision loss in hyperglycemic zebrafish. Fish were [...] Read more.

The present study induced prolonged hyperglycemia (a hallmark symptom of Type 2 diabetes [T2DM]) in Danio rerio (zebrafish) for eight or twelve weeks. The goal of this research was to study cognitive decline as well as vision loss in hyperglycemic zebrafish. Fish were submerged in glucose for eight or twelve weeks, after which they were assessed with both a cognitive assay (three-chamber choice) and a visual assay (optomotor response (OMR)). Zebrafish were also studied during recovery from hyperglycemia. Here, fish were removed from the hyperglycemic environment for 4 weeks after either 4 or 8 weeks in glucose, and cognition and vision was again assessed. The 8- and 12-week cognitive results revealed that water-treated fish showed evidence of learning while glucose- and mannitol-treated fish did not within the three-day testing period. OMR results identified an osmotic effect with glucose-treated fish having significantly fewer positive rotations than water-treated fish but comparable rotations to mannitol-treated fish. The 8- and 12-week recovery results showed that 4 weeks was not enough time to fully recovery from the hyperglycemic insult sustained. Full article

(This article belongs to the Special Issue Zebrafish as a Model in Human Disease)

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17 pages, 2528 KiB

Open AccessArticle

eif4ebp3l—A New Affector of Zebrafish Angiogenesis and Heart Regeneration?

by Lisa I. Born, Theresa Andree, Svenja Frank, Judith Hübner, Sandra Link, Marion Langheine, Anne Charlet, Jennifer S. Esser, Ralph Brehm and Martin Moser

Int. J. Mol. Sci. 2022, 23(17), 10075; https://doi.org/10.3390/ijms231710075 - 03 Sep 2022

Viewed by 1695

Abstract

The eukaryotic initiation factor 4E binding protein (4E-BP) family is involved in translational control of cell proliferation and pro-angiogenic factors. The zebrafish eukaryotic initiation factor 4E binding protein 3 like (eif4ebp3l) is a member of the 4E-BPs and responsible for activity-dependent [...] Read more.

The eukaryotic initiation factor 4E binding protein (4E-BP) family is involved in translational control of cell proliferation and pro-angiogenic factors. The zebrafish eukaryotic initiation factor 4E binding protein 3 like (eif4ebp3l) is a member of the 4E-BPs and responsible for activity-dependent myofibrillogenesis, but whether it affects cardiomyocyte (CM) proliferation or heart regeneration is unclear. We examined eif4ebp3l during zebrafish vascular development and heart regeneration post cryoinjury in adult zebrafish. Using morpholino injections we induced silencing of eif4ebp3l in zebrafish embryos, which led to increased angiogenesis at 94 h post fertilization (hpf). For investigation of eif4ebp3l in cardiac regeneration, zebrafish hearts were subjected to cryoinjury. Regenerating hearts were analyzed at different time points post-cryoinjury for expression of eif4ebp3l by in situ hybridization and showed strongly decreased eif4ebp3l expression in the injured area. We established a transgenic zebrafish strain, which overexpressed eif4ebp3l under the control of a heat-shock dependent promotor. Overexpression of eif4ebp3l during zebrafish heart regeneration caused only macroscopically a reduced amount of fibrin at the site of injury. Overall, these findings demonstrate that silencing of eif4ebp3l has pro-angiogenic properties in zebrafish vascular development and when eif4ebp3l is overexpressed, fibrin deposition tends to be altered in zebrafish cardiac regeneration after cryoinjury. Full article

(This article belongs to the Special Issue Zebrafish as a Model in Human Disease)

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30 pages, 6454 KiB

Open AccessArticle

Transgenic Overexpression of Myocilin Leads to Variable Ocular Anterior Segment and Retinal Alterations Associated with Extracellular Matrix Abnormalities in Adult Zebrafish

by Raquel Atienzar-Aroca, Jesús-José Ferre-Fernández, Angel Tevar, Juan-Manuel Bonet-Fernández, María-José Cabañero, María-José Ruiz-Pastor, Nicolás Cuenca, José-Daniel Aroca-Aguilar and Julio Escribano

Int. J. Mol. Sci. 2022, 23(17), 9989; https://doi.org/10.3390/ijms23179989 - 01 Sep 2022

Cited by 3 | Viewed by 2932

Abstract

Myocilin is an enigmatic glaucoma-associated glycoprotein whose biological role remains incompletely understood. To gain novel insight into its normal function, we used transposon-mediated transgenesis to generate the first zebrafish line stably overexpressing myocilin [Tg(actb1:myoc-2A-mCherry)]. qPCR showed an approximately four-fold increased myocilin expression in [...] Read more.

Myocilin is an enigmatic glaucoma-associated glycoprotein whose biological role remains incompletely understood. To gain novel insight into its normal function, we used transposon-mediated transgenesis to generate the first zebrafish line stably overexpressing myocilin [Tg(actb1:myoc-2A-mCherry)]. qPCR showed an approximately four-fold increased myocilin expression in transgenic zebrafish embryos (144 hpf). Adult (13 months old) transgenic animals displayed variable and age-dependent ocular anterior segment alterations. Almost 60% of two-year-old male, but not female, transgenic zebrafish developed enlarged eyes with severe asymmetrical and variable abnormalities in the anterior segment, characterized by corneal limbus hypertrophy, and thickening of the cornea, iris, annular ligament and lens capsule. The most severe phenotype presented small or absent ocular anterior chamber and pupils, due to iris overgrowth along with dysplastic retinal growth and optic nerve hypertrophy. Immunohistochemistry revealed increased presence of myocilin in most altered ocular tissues of adult transgenic animals, as well as signs of retinal gliosis and expanded ganglion cells and nerve fibers. The preliminary results indicate that these cells contributed to retinal dysplasia. Visual impairment was demonstrated in all old male transgenic zebrafish. Transcriptomic analysis of the abnormal transgenic eyes identified disrupted expression of genes involved in lens, muscular and extracellular matrix activities, among other processes. In summary, the developed transgenic zebrafish provides a new tool to investigate this puzzling protein and provides evidence for the role of zebrafish myocilin in ocular anterior segment and retinal biology, through the influence of extracellular matrix organization and cellular proliferation. Full article

(This article belongs to the Special Issue Zebrafish as a Model in Human Disease)

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20 pages, 34160 KiB

Open AccessArticle

Transcriptome Profile Identifies Actin as an Essential Regulator of Cardiac Myosin Binding Protein C3 Hypertrophic Cardiomyopathy in a Zebrafish Model

by Sahar Isa Da’as, Waseem Hasan, Rola Salem, Nadine Younes, Doua Abdelrahman, Iman A. Mohamed, Arwa Aldaalis, Ramzi Temanni, Lisa Sara Mathew, Stephan Lorenz, Magdi Yacoub, Michail Nomikos, Gheyath K. Nasrallah and Khalid A. Fakhro

Int. J. Mol. Sci. 2022, 23(16), 8840; https://doi.org/10.3390/ijms23168840 - 09 Aug 2022

Cited by 1 | Viewed by 2326

Abstract

Variants in cardiac myosin-binding protein C (cMyBP-C) are the leading cause of inherited hypertrophic cardiomyopathy (HCM), demonstrating the key role that cMyBP-C plays in the heart’s contractile machinery. To investigate the c-MYBPC3 HCM-related cardiac impairment, we generated a zebrafish mypbc3-knockout model. These [...] Read more.

Variants in cardiac myosin-binding protein C (cMyBP-C) are the leading cause of inherited hypertrophic cardiomyopathy (HCM), demonstrating the key role that cMyBP-C plays in the heart’s contractile machinery. To investigate the c-MYBPC3 HCM-related cardiac impairment, we generated a zebrafish mypbc3-knockout model. These knockout zebrafish displayed significant morphological heart alterations related to a significant decrease in ventricular and atrial diameters at systolic and diastolic states at the larval stages. Immunofluorescence staining revealed significant hyperplasia in the mutant’s total cardiac and ventricular cardiomyocytes. Although cardiac contractility was similar to the wild-type control, the ejection fraction was significantly increased in the mypbc3 mutants. At later stages of larval development, the mutants demonstrated an early cardiac phenotype of myocardium remodeling, concurrent cardiomyocyte hyperplasia, and increased ejection fraction as critical processes in HCM initiation to counteract the increased ventricular myocardial wall stress. The examination of zebrafish adults showed a thickened ventricular cardiac wall with reduced heart rate, swimming speed, and endurance ability in both the mypbc3 heterozygous and homozygous groups. Furthermore, heart transcriptome profiling showed a significant downregulation of the actin-filament-based process, indicating an impaired actin cytoskeleton organization as the main dysregulating factor associated with the early ventricular cardiac hypertrophy in the zebrafish mypbc3 HCM model. Full article

(This article belongs to the Special Issue Zebrafish as a Model in Human Disease)

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20 pages, 4824 KiB

Open AccessArticle

Trehalose Treatment in Zebrafish Model of Lafora Disease

by Stefania Della Vecchia, Asahi Ogi, Rosario Licitra, Francesca Abramo, Gabriele Nardi, Serena Mero, Silvia Landi, Roberta Battini, Federico Sicca, Gian Michele Ratto, Filippo Maria Santorelli and Maria Marchese

Int. J. Mol. Sci. 2022, 23(12), 6874; https://doi.org/10.3390/ijms23126874 - 20 Jun 2022

Cited by 9 | Viewed by 2597

Abstract

Mutations in the EPM2A gene encoding laforin cause Lafora disease (LD), a progressive myoclonic epilepsy characterized by drug-resistant seizures and progressive neurological impairment. To date, rodents are the only available models for studying LD; however, their use for drug screening is limited by [...] Read more.

Mutations in the EPM2A gene encoding laforin cause Lafora disease (LD), a progressive myoclonic epilepsy characterized by drug-resistant seizures and progressive neurological impairment. To date, rodents are the only available models for studying LD; however, their use for drug screening is limited by regulatory restrictions and high breeding costs. To investigate the role of laforin loss of function in early neurodevelopment, and to screen for possible new compounds for treating the disorder, we developed a zebrafish model of LD. Our results showed the epm2a^−/− zebrafish to be a faithful model of LD, exhibiting the main disease features, namely motor impairment and neuronal hyperexcitability with spontaneous seizures. The model also showed increased inflammatory response and apoptotic death, as well as an altered autophagy pathway that occurs early in development and likely contributes to the disease progression. Early administration of trehalose was found to be effective for rescuing motor impairment and neuronal hyperexcitability associated with seizures. Our study adds a new tool for investigating LD and might help to identify new treatment opportunities. Full article

(This article belongs to the Special Issue Zebrafish as a Model in Human Disease)

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Review

Jump to: Research

27 pages, 1186 KiB

Open AccessReview

Modeling Human Muscular Dystrophies in Zebrafish: Mutant Lines, Transgenic Fluorescent Biosensors, and Phenotyping Assays

by Chiara Tesoriero, Francesca Greco, Elena Cannone, Francesco Ghirotto, Nicola Facchinello, Marco Schiavone and Andrea Vettori

Int. J. Mol. Sci. 2023, 24(9), 8314; https://doi.org/10.3390/ijms24098314 - 05 May 2023

Cited by 5 | Viewed by 2642

Abstract

Muscular dystrophies (MDs) are a heterogeneous group of myopathies characterized by progressive muscle weakness leading to death from heart or respiratory failure. MDs are caused by mutations in genes involved in both the development and organization of muscle fibers. Several animal models harboring [...] Read more.

Muscular dystrophies (MDs) are a heterogeneous group of myopathies characterized by progressive muscle weakness leading to death from heart or respiratory failure. MDs are caused by mutations in genes involved in both the development and organization of muscle fibers. Several animal models harboring mutations in MD-associated genes have been developed so far. Together with rodents, the zebrafish is one of the most popular animal models used to reproduce MDs because of the high level of sequence homology with the human genome and its genetic manipulability. This review describes the most important zebrafish mutant models of MD and the most advanced tools used to generate and characterize all these valuable transgenic lines. Zebrafish models of MDs have been generated by introducing mutations to muscle-specific genes with different genetic techniques, such as (i) N-ethyl-N-nitrosourea (ENU) treatment, (ii) the injection of specific morpholino, (iii) tol2-based transgenesis, (iv) TALEN, (v) and CRISPR/Cas9 technology. All these models are extensively used either to study muscle development and function or understand the pathogenetic mechanisms of MDs. Several tools have also been developed to characterize these zebrafish models by checking (i) motor behavior, (ii) muscle fiber structure, (iii) oxidative stress, and (iv) mitochondrial function and dynamics. Further, living biosensor models, based on the expression of fluorescent reporter proteins under the control of muscle-specific promoters or responsive elements, have been revealed to be powerful tools to follow molecular dynamics at the level of a single muscle fiber. Thus, zebrafish models of MDs can also be a powerful tool to search for new drugs or gene therapies able to block or slow down disease progression. Full article

(This article belongs to the Special Issue Zebrafish as a Model in Human Disease)

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26 pages, 4975 KiB

Open AccessReview

Zebra-Sphinx: Modeling Sphingolipidoses in Zebrafish

by Luca Mignani, Jessica Guerra, Marzia Corli, Davide Capoferri and Marco Presta

Int. J. Mol. Sci. 2023, 24(5), 4747; https://doi.org/10.3390/ijms24054747 - 01 Mar 2023

Cited by 2 | Viewed by 3059

Abstract

Sphingolipidoses are inborn errors of metabolism due to the pathogenic mutation of genes that encode for lysosomal enzymes, transporters, or enzyme cofactors that participate in the sphingolipid catabolism. They represent a subgroup of lysosomal storage diseases characterized by the gradual lysosomal accumulation of [...] Read more.

Sphingolipidoses are inborn errors of metabolism due to the pathogenic mutation of genes that encode for lysosomal enzymes, transporters, or enzyme cofactors that participate in the sphingolipid catabolism. They represent a subgroup of lysosomal storage diseases characterized by the gradual lysosomal accumulation of the substrate(s) of the defective proteins. The clinical presentation of patients affected by sphingolipid storage disorders ranges from a mild progression for some juvenile- or adult-onset forms to severe/fatal infantile forms. Despite significant therapeutic achievements, novel strategies are required at basic, clinical, and translational levels to improve patient outcomes. On these bases, the development of in vivo models is crucial for a better understanding of the pathogenesis of sphingolipidoses and for the development of efficacious therapeutic strategies. The teleost zebrafish (Danio rerio) has emerged as a useful platform to model several human genetic diseases owing to the high grade of genome conservation between human and zebrafish, combined with precise genome editing and the ease of manipulation. In addition, lipidomic studies have allowed the identification in zebrafish of all of the main classes of lipids present in mammals, supporting the possibility to model diseases of the lipidic metabolism in this animal species with the advantage of using mammalian lipid databases for data processing. This review highlights the use of zebrafish as an innovative model system to gain novel insights into the pathogenesis of sphingolipidoses, with possible implications for the identification of more efficacious therapeutic approaches. Full article

(This article belongs to the Special Issue Zebrafish as a Model in Human Disease)

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21 pages, 1092 KiB

Open AccessReview

Using Zebrafish Animal Model to Study the Genetic Underpinning and Mechanism of Arrhythmogenic Cardiomyopathy

by Yujuan Niu, Yuanchao Sun, Yuting Liu, Ke Du, Xiaolei Xu and Yonghe Ding

Int. J. Mol. Sci. 2023, 24(4), 4106; https://doi.org/10.3390/ijms24044106 - 18 Feb 2023

Viewed by 1925

Abstract

Arrhythmogenic cardiomyopathy (ACM) is largely an autosomal dominant genetic disorder manifesting fibrofatty infiltration and ventricular arrhythmia with predominantly right ventricular involvement. ACM is one of the major conditions associated with an increased risk of sudden cardiac death, most notably in young individuals and [...] Read more.

Arrhythmogenic cardiomyopathy (ACM) is largely an autosomal dominant genetic disorder manifesting fibrofatty infiltration and ventricular arrhythmia with predominantly right ventricular involvement. ACM is one of the major conditions associated with an increased risk of sudden cardiac death, most notably in young individuals and athletes. ACM has strong genetic determinants, and genetic variants in more than 25 genes have been identified to be associated with ACM, accounting for approximately 60% of ACM cases. Genetic studies of ACM in vertebrate animal models such as zebrafish (Danio rerio), which are highly amenable to large-scale genetic and drug screenings, offer unique opportunities to identify and functionally assess new genetic variants associated with ACM and to dissect the underlying molecular and cellular mechanisms at the whole-organism level. Here, we summarize key genes implicated in ACM. We discuss the use of zebrafish models, categorized according to gene manipulation approaches, such as gene knockdown, gene knock-out, transgenic overexpression, and CRISPR/Cas9-mediated knock-in, to study the genetic underpinning and mechanism of ACM. Information gained from genetic and pharmacogenomic studies in such animal models can not only increase our understanding of the pathophysiology of disease progression, but also guide disease diagnosis, prognosis, and the development of innovative therapeutic strategies. Full article

(This article belongs to the Special Issue Zebrafish as a Model in Human Disease)

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18 pages, 1513 KiB

Open AccessReview

Current State of Modeling Human Psychiatric Disorders Using Zebrafish

by Fabiano V. Costa, Tatiana O. Kolesnikova, David S. Galstyan, Nikita P. Ilyin, Murilo S. de Abreu, Elena V. Petersen, Konstantin A. Demin, Konstantin B. Yenkoyan and Allan V. Kalueff

Int. J. Mol. Sci. 2023, 24(4), 3187; https://doi.org/10.3390/ijms24043187 - 06 Feb 2023

Cited by 5 | Viewed by 2517

Abstract

Psychiatric disorders are highly prevalent brain pathologies that represent an urgent, unmet biomedical problem. Since reliable clinical diagnoses are essential for the treatment of psychiatric disorders, their animal models with robust, relevant behavioral and physiological endpoints become necessary. Zebrafish (Danio rerio) [...] Read more.

Psychiatric disorders are highly prevalent brain pathologies that represent an urgent, unmet biomedical problem. Since reliable clinical diagnoses are essential for the treatment of psychiatric disorders, their animal models with robust, relevant behavioral and physiological endpoints become necessary. Zebrafish (Danio rerio) display well-defined, complex behaviors in major neurobehavioral domains which are evolutionarily conserved and strikingly parallel to those seen in rodents and humans. Although zebrafish are increasingly often used to model psychiatric disorders, there are also multiple challenges with such models as well. The field may therefore benefit from a balanced, disease-oriented discussion that considers the clinical prevalence, the pathological complexity, and societal importance of the disorders in question, and the extent of its detalization in zebrafish central nervous system (CNS) studies. Here, we critically discuss the use of zebrafish for modeling human psychiatric disorders in general, and highlight the topics for further in-depth consideration, in order to foster and (re)focus translational biological neuroscience research utilizing zebrafish. Recent developments in molecular biology research utilizing this model species have also been summarized here, collectively calling for a wider use of zebrafish in translational CNS disease modeling. Full article

(This article belongs to the Special Issue Zebrafish as a Model in Human Disease)

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24 pages, 1734 KiB

Open AccessReview

Zebrafish Cancer Avatars: A Translational Platform for Analyzing Tumor Heterogeneity and Predicting Patient Outcomes

by Majd A. Al-Hamaly, Logan T. Turner, Angelica Rivera-Martinez, Analiz Rodriguez and Jessica S. Blackburn

Int. J. Mol. Sci. 2023, 24(3), 2288; https://doi.org/10.3390/ijms24032288 - 24 Jan 2023

Cited by 8 | Viewed by 2529

Abstract

The increasing number of available anti-cancer drugs presents a challenge for oncologists, who must choose the most effective treatment for the patient. Precision cancer medicine relies on matching a drug with a tumor’s molecular profile to optimize the therapeutic benefit. However, current precision [...] Read more.

The increasing number of available anti-cancer drugs presents a challenge for oncologists, who must choose the most effective treatment for the patient. Precision cancer medicine relies on matching a drug with a tumor’s molecular profile to optimize the therapeutic benefit. However, current precision medicine approaches do not fully account for intra-tumoral heterogeneity. Different mutation profiles and cell behaviors within a single heterogeneous tumor can significantly impact therapy response and patient outcomes. Patient-derived avatar models recapitulate a patient’s tumor in an animal or dish and provide the means to functionally assess heterogeneity’s impact on drug response. Mouse xenograft and organoid avatars are well-established, but the time required to generate these models is not practical for clinical decision-making. Zebrafish are emerging as a time-efficient and cost-effective cancer avatar model. In this review, we highlight recent developments in zebrafish cancer avatar models and discuss the unique features of zebrafish that make them ideal for the interrogation of cancer heterogeneity and as part of precision cancer medicine pipelines. Full article

(This article belongs to the Special Issue Zebrafish as a Model in Human Disease)

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21 pages, 820 KiB

Open AccessReview

One Host-Multiple Applications: Zebrafish (Danio rerio) as Promising Model for Studying Human Cancers and Pathogenic Diseases

by Karolina Dudziak, Michał Nowak and Magdalena Sozoniuk

Int. J. Mol. Sci. 2022, 23(18), 10255; https://doi.org/10.3390/ijms231810255 - 06 Sep 2022

Cited by 5 | Viewed by 2513

Abstract

In recent years, zebrafish (ZF) has been increasingly applied as a model in human disease studies, with a particular focus on cancer. A number of advantages make it an attractive alternative for mice widely used so far. Due to the many advantages of [...] Read more.

In recent years, zebrafish (ZF) has been increasingly applied as a model in human disease studies, with a particular focus on cancer. A number of advantages make it an attractive alternative for mice widely used so far. Due to the many advantages of zebrafish, modifications can be based on different mechanisms and the induction of human disease can take different forms depending on the research goal. Genetic manipulation, tumor transplantation, or injection of the pathogen are only a few examples of using ZF as a model. Most of the studies are conducted in order to understand the disease mechanism, monitor disease progression, test new or alternative therapies, and select the best treatment. The transplantation of cancer cells derived from patients enables the development of personalized medicine. To better mimic a patient’s body environment, immune-deficient models (SCID) have been developed. A lower immune response is mostly generated by genetic manipulation but also by irradiation or dexamethasone treatment. For many studies, using SCID provides a better chance to avoid cancer cell rejection. In this review, we describe the main directions of using ZF in research, explain why and how zebrafish can be used as a model, what kind of limitations will be met and how to overcome them. We collected recent achievements in this field, indicating promising perspectives for the future. Full article

(This article belongs to the Special Issue Zebrafish as a Model in Human Disease)

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Zebrafish as a Model in Human Disease

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