Serum vitamin C levels modulate the lifespan and endoplasmic reticulum stress response pathways in mice synthesizing a nonfunctional mutant WRN protein

Abstract

Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-family DNA helicase (WRN). Mice lacking part of the helicase domain of the WRN ortholog exhibit several phenotypic features of WS. In this study, we generated a Wrn mutant line that, like humans, relies entirely on dietary sources of vitamin C (ascorbate) to survive, by crossing them to mice that lack the gulonolactone oxidase enzyme required for ascorbate synthesis. In the presence of 0.01% ascorbate (w/v) in drinking water, double-mutant mice exhibited a severe reduction in lifespan, small size, sterility, osteopenia, and metabolic profiles different from wild-type (WT) mice. Although increasing the dose of ascorbate to 0.4% improved dramatically the phenotypes of double-mutant mice, the metabolic and cytokine profiles were different from age-matched WT mice. Finally, double-mutant mice treated with 0.01% ascorbate revealed a permanent activation of all the 3 branches of the ER stress response pathways due to a severe chronic oxidative stress in the ER compartment. In addition, markers associated with the ubiquitin-proteasome-dependent ER-associated degradation pathway were increased. Augmenting the dose of ascorbate reversed the activation of this pathway to WT levels rendering this pathway a potential therapeutic target in WS.-Aumailley, L., Dubois, M. J., Brennan, T. A., Garand, C., Paquet, E. R., Pignolo, R. J., Marette, A., Lebel, M. Serum vitamin C levels modulate the lifespan and endoplasmic reticulum stress response pathways in mice synthesizing a nonfunctional mutant WRN protein.

COPB2 loss of function causes a coatopathy with osteoporosis and developmental delay

“…Ascorbic acid is known to stimulate collagen synthesis and secretion, 16,46 enhance healing of fractured bones in preclinical studies, 58 and significantly decrease the risk of osteoporosis and hip fracture in adults. 59,60 Interestingly, it is also implicated in protein homeostasis in the ER, [47][48][49] and our data suggest that the ER and Golgi dysfunction may be rescued by treatment with ascorbic acid. These experiments support the use of ascorbic acid as a therapeutic modality for improvement of bone fragility in individuals with COPB2 deficiency and provide a mechanistic rationale for its potential positive effects.…”

“…7,16,46 In addition, ascorbic acid has been implicated in protein homeostasis in the ER and in regulating the ER stress response. [47][48][49] Given the essential role of ascorbic acid in PC metabolism, and its potential role as a modulator of proteostasis and ER stress, the effect of ascorbic acid supplementation was studied in the COPB2-deficient animal models. Ascorbic acid treatment rescued type II collagen secretion in copb2 b1327/b1327 homozygous zebrafish mutant embryos in a dose-dependent manner (Figures 6B, 6D, and 6F and Figure S8).…”

Calcification in Werner syndrome associated with lymphatic vessels aging

“…Although, to date, various types of mutations in the WRN gene are in WS patients, while mutated proteins generally lack nuclear localization signals [ 2 , 18 – 20 ]. Supporting this hypothesis, earlier studies using knock-in mice have shown that WRN mutant proteins accumulated in the cytoplasm of WRN mutant mice cause oxidative stress in the cells, resulting in various symptoms associated with aging [ 21 – 23 ]. However, the phenotype in WS patients does not appear in the knock-out mice lacking the WRN gene.…”