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WRN loss accelerates abnormal adipocyte metabolism in Werner Syndrome

ABSTRACT: Metabolic dysfunction is one of the main symptoms of Werner syndrome (WS); however, the underlying mechanisms remain unclear. Here, we report that loss of WRN accelerates adipogenesis at an early stage both in vitro (stem cells) and in vivo (zebrafish). Moreover, WRN depletion causes a transient upregulation of late-stage of adipocyte-specific genes at an early stage.

ORGANISM(S): Homo sapiens

PROVIDER: GSE248012 | GEO | 2024/01/26

REPOSITORIES: GEO

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WRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome [RNA-seq]

Project description:Werner Syndrome (WS) is an autosomal recessive disorder characterized by premature aging due to mutations of the WRN gene. A classical sign in WS patients is short stature, but the underlying mechanisms are not well understood. Here we report that WRN is indispensable for chondrogenesis, which is the engine driving the elongation of bones and determines height.

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Project description:Werner syndrome (WS) is an adult-onset progeroid syndrome characterized by accelerated aging. The International Registry of Werner Syndrome in the Department of Pathology, University of Washington, collects WS cases from all over the world. Classical WS is caused by WRN mutations. Those who do not carry WRN are categorized as "atypical Werner syndrome." A small subset of atypical WS is caused by LMNA mutations. There also are many cases whose causes are still unknown. The purpose of this study is to identify other causative gene(s) of atypical WS.

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NAD+ repletion inhibits accelerated aging in Werner syndrome through the restoration of mitophagy

Project description:Metabolic dysfunction is a primary feature of the premature aging Werner syndrome (WS), a heritable human disease caused by mutations in the gene encoding the DNA helicase Werner (WRN). However, the relationship between WRN mutation and its severe metabolic phenotypes is unclear. Here we report mitochondrial dysfunction and depletion of NAD+, a fundamental ubiquitous cofactor, in WS patient samples and WS animal models. NAD+ repletion restores NAD+ metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD+ repletion remarkably delays accelerated aging, including stem cell dysfunction in both C. elegans and Drosophila models of WS. Mechanistically, WRN physically binds to a key NAD+ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) and facilitates its NAD+ production. Our findings reveal an unprecedented anti-aging mechanism of WRN that integrates its new function of NAD+ synthesis to coordinate mitochondrial maintenance and energy expenditure, and suggest therapeutic potential.

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Expression data from Werner syndrome iPSCs

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Gene expression profiling in the liver of 3-month old mice with a mutant Wrn protein treated with vitamin C compared to the liver of 3-month old untreated mice with a mutant Wrn protein.

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