Abstract
Werner syndrome (WS), caused by mutations at the WRN helicase gene, is a progeroid syndrome characterized by multiple features consistent with accelerated aging. Aberrant double-strand DNA damage repair leads to genomic instability and reduced replicative lifespan of somatic cells. We observed increased autophagy in WRN knockdown cells; this was further increased by short-term rapamycin treatment. Long-term rapamycin treatment resulted in improved growth rate, reduced accumulation of DNA damage foci and improved nuclear morphology; autophagy markers were reduced to near-normal levels, possibly due to clearance of damaged proteins. These data suggest that protein aggregation plays a role in the development of WS phenotypes and that the mammalian target of rapamycin complex 1 pathway is a potential therapeutic target of WS.
Highlights
The levels of the mature autophagosome marker, LC3-II, and of LC3-II/LC3-I ratios were increased in WRN knockdown cells as compared with a (A)
Our initial study using Werner syndrome (WS) patient fibroblasts showed increased autophagy in primary and catalytic subunit of human telomerase-immortalized cells; these levels were further increased by rapamycin treatment
LC3-II and the LC3-II/LC3-I ratio were both increased in WRN knockdown cells compared with untreated cells, indicating stimulation of autophagy (Fig. 1B,C)
Summary
The levels of the mature autophagosome marker, LC3-II, and of LC3-II/LC3-I ratios were increased in WRN knockdown cells as compared with a (A) A specific inhibitor of mTOR complex 1 (mTORC1), activates autophagy to facilitate degradation of cellular damaged protein aggregates and organelles to improve cellular function and extend lifespan (Johnson et al, 2013). Our initial study using WS patient fibroblasts showed increased autophagy in primary and catalytic subunit of human telomerase (hTERT)-immortalized cells; these levels were further increased by rapamycin treatment (data not shown). LC3-II and the LC3-II/LC3-I ratio were both increased in WRN knockdown cells compared with untreated cells, indicating stimulation of autophagy (Fig. 1B,C).
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