Peroxiredoxin 5 Silencing Sensitizes Dopaminergic Neuronal Cells to Rotenone via DNA Damage-Triggered ATM/p53/PUMA Signaling-Mediated Apoptosis

Abstract

Peroxiredoxins (Prxs) are a family of thioredoxin peroxidases. Accumulating evidence suggests that changes in the expression of Prxs may be involved in neurodegenerative diseases pathology. However, the expression and function of Prxs in Parkinson's disease (PD) remains unclear.Here, we showed that Prx5 was the most downregulated of the six Prx subtypes in dopaminergic (DA) neurons in rotenone-induced cellular and rat models of PD, suggesting possible roles in regulating their survival. Depletion of Prx5 sensitized SH-SY5Y DA neuronal cells to rotenone-induced apoptosis. The extent of mitochondrial membrane potential collapse, cytochrome c release, and caspase activation was increased by Prx5 loss. Furthermore, Prx5 knockdown enhanced the induction of PUMA by rotenone through a p53-dependent mechanism. Using RNA interference approaches, we demonstrated that the p53/PUMA signaling was essential for Prx5 silencing-exacerbated mitochondria-driven apoptosis. Additionally, downregulation of Prx5 augmented rotenone-induced DNA damage manifested as induction of phosphorylated histone H2AX (γ-H2AX) and activation of ataxia telangiectasia mutated (ATM) kinase. The pharmacological inactivation of ATM revealed that ATM was integral to p53 activation by DNA damage. These findings provided a novel link between Prx5 and DNA damage-triggered ATM/p53/PUMA signaling in a rotenone-induced PD model. Thus, Prx5 might play an important role in protection against rotenone-induced DA neurodegeneration.Cells 2020, 9, 22 2 of 25 ubiquitin-proteasome system, and autophagy-lysosome pathway may be involved in the pathogenesis of PD [3,4]. Recently, DNA damage is hypothesized to constitute a unifying component across different neurodegenerative diseases [5]. Increased DNA strand breaks and oxidative DNA damages have been found in the SN and peripheral blood of PD patients [6][7][8], suggesting that DNA damage may compromise genomic integrity leading to the onset of PD [9].Peroxiredoxins (Prxs) represent a superfamily of thiol-dependent antioxidant enzymes that participate directly in eliminating H 2 O 2 and regulate the transduction of various cellular signals by modulating redox signaling [10,11]. In mammals, six isoforms of Prxs have been identified, comprising typical 2-Cys Prxs (Prx1-4), atypical 2-Cys Prxs (Prx5), and 1-Cys Prxs (Prx6). Proposed functions of Prxs include regulation of cellular proliferation, differentiation, immune responses, and apoptosis [12]. Prx5 is broadly localized in the cytosol, mitochondria, peroxisome, and nucleus, and performs specific functions according to its subcellular localization [13]. Initially, Prx5 was described as a DNA-binding protein able to suppress RNA polymerase III-dependent transcription of Alu retroposons in vitro [14]. The cytoprotective antioxidant function of Prx5 has been investigated after human Prx5 was characterized as a peroxidase but also because of the existence of this enzyme in peroxisomes and mitochondria, the two major places of reactive oxygen species (ROS)/reactive nitrogen ...

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