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| Open AccessDevelopment and rescue of human familial hypercholesterolaemia in a xenograft mouse model
Familial hypercholesterolemia (FH) is a congenital disease associated with high plasma cholesterol levels. Here, the authors recapitulate FH in chimeric mice, in which livers are repopulated with hepatocytes from an FH patient, and successfully correct the disease using adenovirus-mediated gene therapy.
- Beatrice Bissig-Choisat
- , Lili Wang
- & Karl-Dimiter Bissig
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| Open AccessGlycine decarboxylase deficiency causes neural tube defects and features of non-ketotic hyperglycinemia in mice
Mutations in the enzyme glycine decarboxylase (GLDC) are associated with neural tube closure defects and non-ketotic hyperglycinemia in humans. Here the authors generate a mouse model with reduced Gldc expression and activity and study the direct effect of the enzyme in these diseases and the mechanisms responsible for neural tube closure defects.
- Yun Jin Pai
- , Kit-Yi Leung
- & Nicholas D.E. Greene
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Coordinated regulatory variation associated with gestational hyperglycaemia regulates expression of the novel hexokinase HKDC1
Maternal glucose levels during pregnancy can affect the metabolic health of a developing fetus, both early on and later in life. Here, the authors reveal that genetic variants in several regulatory elements alter glucose homeostasis during pregnancy by reducing the expression of a novel hexokinase gene, HKDC1.
- Cong Guo
- , Anton E. Ludvik
- & Timothy E. Reddy
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A non-conserved miRNA regulates lysosomal function and impacts on a human lysosomal storage disorder
Multiple sulfatase deficiency is a lysosomal storage disorder arising from mutations in the sulfatase modifying factor 1 (SUMF1) gene. Here Frankel et al. show that targeting a microRNA, miR-95, can increase residual SUMF1 expression and restore sulfatase activity in patient cells.
- Lisa B. Frankel
- , Chiara Di Malta
- & Anders H. Lund
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Article
| Open AccessMitochondrial protein sorting as a therapeutic target for ATP synthase disorders
Effective treatment options for mitochondrial diseases are scarce. Here, Aiyar et al. identify the TIM23 mitochondrial protein sorting machinery as a potential intervention point for mitochondrial ATP synthase disorders.
- Raeka S. Aiyar
- , Maria Bohnert
- & Lars M. Steinmetz
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Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis
Iron deficiency is the leading cause of anaemia and is known to compromise immune function. Here, the authors identify several new genes associated with iron status in European populations and provide insight into how iron levels may be linked to the risk of metabolic disease.
- Beben Benyamin
- , Tonu Esko
- & John B. Whitfield
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IL-37 protects against obesity-induced inflammation and insulin resistance
Inflammation is a hallmark of obesity and driver of various associated pathologies. Here the authors show that mice overexpressing the anti-inflammatory cytokine IL-37 are protected from the metabolic consequences of a high-fat diet, and that plasma levels of IL-37 correlate with insulin sensitivity in humans.
- Dov B. Ballak
- , Janna A. van Diepen
- & Rinke Stienstra
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A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV
Mucolipidosis type IV is a lysosomal storage disorder caused by mutations in the endolysosomal cation channel TRPML1 and results in progressive neurodegeneration. Here, Chen et al. demonstrate that small molecules can be used to restore TRPML1 mutant channel function and rescue disease-associated symptoms.
- Cheng-Chang Chen
- , Marco Keller
- & Christian Grimm
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iPSC-derived neurons from GBA1-associated Parkinson’s disease patients show autophagic defects and impaired calcium homeostasis
Mutations in the gene, GBA1, cause Gaucher’s disease, and are a strong risk factor for the development of Parkinson’s disease. Here the authors use cells derived from Parkinson’s patients with GBA1mutations to model the disease, and reveal changes in cellular recycling systems that may promote neurodegeneration.
- David C. Schöndorf
- , Massimo Aureli
- & Michela Deleidi
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High-fat maternal diet during pregnancy persistently alters the offspring microbiome in a primate model
The influence of diet on the establishment of gut microbiota early in life is poorly understood. Here the authors show, in a primate model, that maternal diet during pregnancy affects the offspring’s microbiome, and that dietary intervention after weaning only partially reverses this effect.
- Jun Ma
- , Amanda L. Prince
- & Kjersti M. Aagaard
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Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction
The adipokine endotrophin promotes tumour inflammation and angiogenesis, but its effects on adipose tissue are unclear. Here, Sun et al.show that endotrophin promotes adipose tissue inflammation and fibrosis, and that injections of an anti-endotrophin antibody improve metabolic parameters of mice on a high-fat diet.
- Kai Sun
- , Jiyoung Park
- & Philipp E. Scherer
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Article
| Open AccessDepleting the methyltransferase Suv39h1 improves DNA repair and extends lifespan in a progeria mouse model
Accelerated cellular ageing in patients with progeria can be caused by the accumulation of nuclear lamins, leading to DNA damage and histone methylation. Here Liu et al. show that the metyltransferase SUV39H1 regulates lamin A stability, and that SUV39H1 depletion extends lifespan in a progeria mouse model.
- Baohua Liu
- , Zimei Wang
- & Zhongjun Zhou
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Tribbles 3 mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle
Endoplasmic reticulum (ER) stress is observed in diabetes and has been linked to insulin resistance in various tissues. Here, Koh and colleagues show the protein Tribbles 3, which is induced by ER stress and obesity in mice and humans, is an inhibitor of insulin signalling in skeletal muscle.
- Ho-Jin Koh
- , Taro Toyoda
- & Laurie J. Goodyear
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Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release
Accumulation of lysosomal lipids is a feature of Niemann'-Picks (NP) disease, but how these lipids contribute to the disease is unclear. In this study, calcium released via the lysosomal TRPML1 channel is shown to be reduced in NP-type C cells, and sphingomyelins are found to inhibit the channel's activity.
- Dongbiao Shen
- , Xiang Wang
- & Haoxing Xu
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| Open AccessMuscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model
The function of adult stem cells is diminished with age but the role this dysfunction plays in the aging process is unknown. Here, the injection of muscle-derived stem/progenitor cells from young mice rescues symptoms in progeroid mice and is shown to regenerate tissues independent of engraftment.
- Mitra Lavasani
- , Andria R. Robinson
- & Johnny Huard
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Pyrimidine pool imbalance induced by BLM helicase deficiency contributes to genetic instability in Bloom syndrome
Mutations in the DNA helicaseBLM cause Bloom syndrome, which is characterized by slow replication fork progression and genetic instability. Here, cells lacking BLMare shown to have a defect in cytidine deaminase, which alters the pyrimidine pool and results in replication fork progression with altered velocity.
- Pauline Chabosseau
- , Géraldine Buhagiar-Labarchède
- & Mounira Amor-Guéret