Mouse Models of Diet-Induced Nonalcoholic Steatohepatitis Reproduce the Heterogeneity of the Human Disease

Abstract A hallmark of neurodegeneration is defective protein quality control. The E3 ligase Listerin (LTN1/Ltn1) acts in a specialized protein quality control pathway—Ribosome-associated Quality Control (RQC)—by mediating proteolytic targeting of incomplete polypeptides produced by ribosome stalling, and Ltn1 mutation leads to neurodegeneration in mice. Whether neurodegeneration results from defective RQC and whether defective RQC contributes to human disease have remained unknown. Here we show that three independently-generated mouse models with mutations in a different component of the RQC complex, NEMF/Rqc2, develop progressive motor neuron degeneration. Equivalent mutations in yeast Rqc2 selectively interfere with its ability to modify aberrant translation products with C-terminal tails which assist with RQC-mediated protein degradation, suggesting a pathomechanism. Finally, we identify NEMF mutations expected to interfere with function in patients from seven families presenting juvenile neuromuscular disease. These uncover NEMF’s role in translational homeostasis in the nervous system and implicate RQC dysfunction in causing neurodegeneration.

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Mouse models of human cancer and the need for more translational research

10.53731/r294649-6f79289-8cwav ◽

2008 ◽

Author(s):

Martin Fenner

Keyword(s):

Mouse Model ◽

Translational Research ◽

Synovial Sarcoma ◽

Mouse Models ◽

Human Disease ◽

Human Cancer ◽

Neuropsychiatric Disorders ◽

International Congress

One of the opening lectures this Saturday of the International Congress of Genetics was held by Mario Capecchi. His talked was entitled Modeling human disease in the mouse: from cancer to neuropsychiatric disorders. In the first half he described his mouse model of synovial sarcoma. ...

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TarGo: network based target gene selection system for human disease related mouse models

Laboratory Animal Research ◽

10.1186/s42826-019-0023-z ◽

2019 ◽

Vol 35 (1) ◽

Author(s):

Daejin Hyung ◽

Ann-Marie Mallon ◽

Dong Soo Kyung ◽

Soo Young Cho ◽

Je Kyung Seong

Keyword(s):

Mouse Models ◽

Network Topology ◽

Human Disease ◽

Target Gene ◽

Gene Selection ◽

Genetically Engineered ◽

Human Diseases ◽

Selection System ◽

Genetically Engineered Mouse Models ◽

Disease Signatures

Abstract Genetically engineered mouse models are used in high-throughput phenotyping screens to understand genotype-phenotype associations and their relevance to human diseases. However, not all mutant mouse lines with detectable phenotypes are associated with human diseases. Here, we propose the “Target gene selection system for Genetically engineered mouse models” (TarGo). Using a combination of human disease descriptions, network topology, and genotype-phenotype correlations, novel genes that are potentially related to human diseases are suggested. We constructed a gene interaction network using protein-protein interactions, molecular pathways, and co-expression data. Several repositories for human disease signatures were used to obtain information on human disease-related genes. We calculated disease- or phenotype-specific gene ranks using network topology and disease signatures. In conclusion, TarGo provides many novel features for gene function prediction.

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An Overview of Mouse Models of Nonalcoholic Steatohepatitis: From Past to Present

Current Protocols in Mouse Biology ◽

10.1002/cpmo.3 ◽

2016 ◽

Vol 6 (2) ◽

pp. 185-200 ◽

Cited By ~ 22

Author(s):

Ans Jacobs ◽

Anne‐Sophie Warda ◽

Jef Verbeek ◽

David Cassiman ◽

Pieter Spincemaille

Keyword(s):

Mouse Models ◽

Nonalcoholic Steatohepatitis

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The Relevance of Genetically Altered Mouse Models of Human Disease

Alternatives to Laboratory Animals ◽

10.1177/026119290603400401 ◽

2006 ◽

Vol 34 (4) ◽

pp. 429-454 ◽

Cited By ~ 3

Author(s):

Nirmala Bhogal ◽

Robert Combes

Keyword(s):

Mouse Models ◽

Human Disease

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Mouse Models of Nonalcoholic Steatohepatitis: Head-to-Head Comparison of Dietary Models and Impact on Inflammation and Animal Welfare

Gastroenterology Research and Practice ◽

10.1155/2020/7347068 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Andreas Kroh ◽

Vanina Ivanova ◽

Hannah Drescher ◽

Julia Andruszkow ◽

Thomas Longerich ◽

...

Keyword(s):

Mouse Model ◽

Animal Welfare ◽

Mouse Models ◽

Nonalcoholic Steatohepatitis ◽

Cell Sorting ◽

High Fat Diet ◽

Histopathological Examination ◽

Clinical Status ◽

Nonalcoholic Fatty Liver ◽

The Impact

A variety of dietary nonalcoholic steatohepatitis (NASH) mouse models are available, and choosing the appropriate mouse model is one of the most important steps in the design of NASH studies. In addition to the histopathological and metabolic findings of NASH, a sufficient mouse model should guarantee a robust clinical status and good animal welfare. Three different NASH diets, a high-fat diet (HFD60), a western diet (WD), and a cafeteria diet (CAFD), were fed for 12 or 16 weeks. Metabolic assessment was conducted at baseline and before scheduled sacrifice, and liver inflammation was analyzed via fluorescence-associated cell sorting and histopathological examination. Clinical health conditions were scored weekly to assess the impact on animal welfare. The HFD60 and WD were identified as suitable NASH mouse models without a significant strain on animal welfare. Furthermore, the progression of inflammation and liver fibrosis was associated with a decreased proportion of CD3+ NK1.1+ cells. The WD represents a model of advanced-stage NASH, and the HFD60 is a strong model of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome. However, the CAFD should not be considered a NASH model.

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