Abstract
Peroxisomes are small, membrane-enclosed eukaryotic organelles that house various enzymes with metabolic functions. One important feature in both Hutchinson-Gilford Progeria Syndrome (HGPS) and normal aging is the elevated levels of Reactive Oxygen Species (ROS), which are generated from metabolic pathways with the capacity to cause oxidative damage to macromolecules within the cells. Although peroxisomal bioreactions can generate free radicals as their byproducts, many metabolic enzymes within the peroxisomes play critical roles as ROS scavengers, in particular, catalase. Here, we observed impaired peroxisomes-targeting protein trafficking, which suggested that the poorly assembled peroxisomes might cause high oxidative stress, contributing to the premature senescent phenotype in HGPS. We then investigated the ROS clearance efficiency by peroxisomal enzymes and found a significantly decreased expression of catalase in HGPS. Furthermore, we evaluated the effects of two promising HGPS-treatment drugs Methylene Blue and RAD001 (Everolimus, a rapamycin analog) on catalase in HGPS fibroblasts. We found that both drugs effectively reduced cellular ROS levels. MB, as a well-known antioxidant, did not affect catalase expression or activity. Interestingly, RAD001 treatment significantly upregulated catalase activity in HGPS cells. Our study presents the first characterization of peroxisomal function in HGPS and provides new insights into the cellular aspects of HGPS and the ongoing clinical trial.
Highlights
Hutchinson-Gilford Progeria Syndrome (HGPS) is a devastating autosomal dominant genetic disorder affecting one in 4-8 million children worldwide [1, 2]
We found that the majority of peroxisomes stained are mature and that there is no significant difference between the PMP70catalase colocalizations in normal and HGPS fibroblasts (Supplementary Figure 1A)
The results acquired from more than 100 cells indicated that compared to normal fibroblasts, there was a larger portion of HGPS cells with higher GFP-SCP2-deficient “peroxisome ghosts” index (Figure 1C, 1D)
Summary
Hutchinson-Gilford Progeria Syndrome (HGPS) is a devastating autosomal dominant genetic disorder affecting one in 4-8 million children worldwide [1, 2]. One defining feature in both HGPS and normal aging is the accumulated cellular oxidative stress, which occurs when there is an imbalance between the production of reactive oxygen species (ROS) and antioxidants that curb ROS initiation and propagation [12]. In HGPS, ROS levels become elevated due to mitochondrial dysfunction, as www.aging-us.com there is a distinct downregulation of mitochondrial oxidative phosphorylation proteins, morphological abnormalities, and lessened movement [9, 10]. Increased levels of ROS can lead to cellular and molecular damage in the body, which is why ROS scavengers in peroxisomes play a key role in the management of oxidative stress [13]. Peroxisomes biogenesis disorders, peroxisomal matrix proteins mislocalization and catalase deficiency have been reported in normal aging cells [16]
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