Research Article: Down regulation of miR-124 in both Werner syndrome DNA helicase mutant mice and mutant Caenorhabditis elegans wrn-1 reveals the importance of this microRNA in accelerated aging

Date Published: September 29, 2012

Publisher: Impact Journals LLC

Author(s): Alexandra Dallaire, Chantal Garand, Eric R. Paquet, Sarah J. Mitchell, Rafael de Cabo, Martin J. Simard, Michel Lebel.



Small non-coding microRNAs are believed to be involved in the mechanism of aging but nothing is known on the impact of microRNAs in the progeroid disorder Werner syndrome (WS). WS is a premature aging disorder caused by mutations in a RecQ-like DNA helicase. Mice lacking the helicase domain of the WRN ortholog exhibit many phenotypic features of WS, including a pro-oxidant status and a shorter mean life span. Caenorhabditis elegans (C. elegans) with a nonfunctional wrn-1 DNA helicase also exhibit a shorter life span. Thus, both models are relevant to study the expression of microRNAs involved in WS. In this study, we show that miR-124 expression is lost in the liver of Wrn helicase mutant mice. Interestingly, the expression of this conserved miR-124 in whole wrn-1 mutant worms is also significantly reduced. The loss of mir-124 in C. elegans increases reactive oxygen species formation and accumulation of the aging marker lipofuscin, reduces whole body ATP levels and results in a reduction in life span. Finally, supplementation of vitamin C normalizes the median life span of wrn-1 and mir-124 mutant worms. These results suggest that biological pathways involving WRN and miR-124 are conserved in the aging process across different species.

Partial Text

Aging is a progressive deterioration of physiological functions impairing the ability of an organism to cope with endogenous or exogenous stresses and maintain homeostasis. This in turn leads to increased susceptibility to diseases and death. The study of human progeroid syndromes have greatly advanced the understanding of the aging process [1]. One fascinating human aging disorder is Werner syndrome (WS). WS is a human autosomal recessive disorder characterized by genomic instability and the premature onset of a number of age-related diseases [2-5]. The defective enzyme responsible for WS possesses a 3′–5′ exonuclease activity in addition to a 3′–5′ helicase activity [6-8] and is involved in DNA repair, replication, transcription, and telomere maintenance [9-13]. We previously generated a mouse model with a deletion in the helicase domain of the murine WRN homologue (hereafter referred as WrnDhel/Dhel) [14] that recapitulates most of the WS phenotypes, including an abnormal hyaluronic acid excretion, higher reactive oxygen species (ROS) levels, dyslipidemia, increased genomic instability, and cancer incidence. Overall, such mutant mice have a 10-15% decreased of their mean life span [15, 16].





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