Abstract
SummaryHutchinson‐Gilford progeria syndrome (HGPS) constitutes a genetic disease wherein an aging phenotype manifests in childhood. Recent studies indicate that reactive oxygen species (ROS) play important roles in HGPS phenotype progression. Thus, pharmacological reduction in ROS levels has been proposed as a potentially effective treatment for patient with this disorder. In this study, we performed high‐throughput screening to find compounds that could reduce ROS levels in HGPS fibroblasts and identified rho‐associated protein kinase (ROCK) inhibitor (Y‐27632) as an effective agent. To elucidate the underlying mechanism of ROCK in regulating ROS levels, we performed a yeast two‐hybrid screen and discovered that ROCK1 interacts with Rac1b. ROCK activation phosphorylated Rac1b at Ser71 and increased ROS levels by facilitating the interaction between Rac1b and cytochrome c. Conversely, ROCK inactivation with Y‐27632 abolished their interaction, concomitant with ROS reduction. Additionally, ROCK activation resulted in mitochondrial dysfunction, whereas ROCK inactivation with Y‐27632 induced the recovery of mitochondrial function. Furthermore, a reduction in the frequency of abnormal nuclear morphology and DNA double‐strand breaks was observed along with decreased ROS levels. Thus, our study reveals a novel mechanism through which alleviation of the HGPS phenotype is mediated by the recovery of mitochondrial function upon ROCK inactivation.
Highlights
Hutchinson-Gilford progeria syndrome (HGPS) represents one of premature aging syndromes wherein patients die at an average age of 12.6 years (Capell et al, 2005)
The present screening strategy consisted of two different methods to evaluate the capacity of restoration in senescent HGPS fibroblasts: (i) reducing reactive oxygen species (ROS) levels and (ii) increasing cell numbers
A library containing 355 kinase inhibitors was added to senescent HGPS fibroblasts, and their effect on ROS levels was determined on day 16 (Fig. 1C and Table S1, Supporting information)
Summary
Hutchinson-Gilford progeria syndrome (HGPS) represents one of premature aging syndromes wherein patients die at an average age of 12.6 years (Capell et al, 2005). The cardinal feature of HGPS is the generation of truncated lamin A protein, which is induced by point mutations in the LMNA gene. This causes irregular/enlarged nuclei and nuclear blebbing (McClintock et al, 2006). Treatment with FTIs is associated with harmful side effects including cytotoxicity and centrosome separation defects (Verstraeten et al, 2011) Given these findings, the use of FTIs alone for the treatment of patients with HGPS has been questioned; there is a need for more effective drugs that can be used alone or in combination with FTIs (Liu et al, 2006)
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