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12 19, 2019;9 (1):

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

Mei-Jen Wang, Hsin-Yi Huang, Tsung-Lang Chiu, Hui-Fen Chang, Hsin-Rong Wu
Author Information
  1. Mei-Jen Wang: Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan.
  2. Hsin-Yi Huang: Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan.
  3. Tsung-Lang Chiu: Division of Neurosurgery, Neuro-Medical Scientific Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan.
  4. Hui-Fen Chang: Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan.
  5. Hsin-Rong Wu: Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan.
PMID: 31861721 DOI: 10.3390/cells9010022

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.

Keywords

ATM DNA damage P53 PUMA Parkinson’s disease dopaminergic neurons peroxiredoxin 5 rotenone γ-H2AX

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Grants

  1. TCRD105-33 and TCRD106-41/Hualien Tzu Chi Hospital, Taiwan
  2. MOST 105-2320-B-303-002-MY3/Ministry of Science and Technology, Taiwan
  3. TCMFRP-106-01-02/Buddhist Tzu Chi Medical Foundation, Taiwan

MeSH Term

Animals
Ataxia Telangiectasia Mutated Proteins
Cell Survival
Cells, Cultured
DNA Damage
Disease Models, Animal
Dopaminergic Neurons
Drug Synergism
Gene Knockdown Techniques
Humans
Male
Parkinson Disease
Peroxiredoxins
Primary Cell Culture
Rats
Rotenone
Signal Transduction
Tumor Suppressor Protein p53
Tumor Suppressor Proteins

Chemicals

Tumor Suppressor Protein p53
Tumor Suppressor Proteins
Rotenone
PRDX5 protein, human
Peroxiredoxins
Prdx5 protein, rat
Ataxia Telangiectasia Mutated Proteins
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 7

Word Cloud

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