Cumulative oxidative damages to cell constituents are considered to contribute to aging and age-related diseases. The enzyme peptide methionine sulfoxide reductase A (MSRA) catalyzes the repair of oxidized methionine in proteins by reducing methionine sulfoxide back to methionine. However, whether MSRA plays a role in the aging process is poorly understood. Here we report that overexpression of the msrA gene predominantly in the nervous system markedly extends the lifespan of the fruit fly Drosophila. The MSRA transgenic animals are more resistant to paraquatinduced oxidative stress, and the onset of senescence-induced decline in the general activity level and reproductive capacity is delayed markedly. The results suggest that oxidative damage is an important determinant of lifespan, and MSRA may be important in increasing the lifespan in other organisms including humans.
Many neurodegenerative diseases, such as frontotemporal dementia (FTD), are associated with behavioral deficits, but the anatomical and molecular bases remain poorly understood. Here we show that forebrain-specific expression of FTD-associated mutant CHMP2B causes several age-dependent neurodegenerative phenotypes, including social behavioral impairments. The social deficits were accompanied by a change in AMPA receptor (AMPAR) composition, leading to imbalance between Ca2+-permeable and -impermeable AMPARs. Expression of most AMPAR subunits was regulated by the brain-enriched microRNA (miR-124), whose abundance was markedly decreased in the superficial layers of cerebral cortex of FTD mice. We found similar changes in miR-124 and AMPAR levels in the frontal cortex and iPSC-derived neurons of subjects with behavioral variant FTD. Moreover, miR-124 expression in the medial prefrontal cortex decreased AMPAR levels and partially rescued behavioral deficits. Knockdown of Gria2 also alleviated social impairments in FTD mice. Our results identify a novel mechanism involving miR-124 and AMAPRs in regulating social behavior in FTD and suggest a potential therapeutic avenue.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.