Uncoupling protein 2 deficiency aggravates astrocytic endoplasmic reticulum stress and nod-like receptor protein 3 inflammasome activation.

Abstract

Astrocytes play crucial roles in determining the susceptibility to oxidative stress in the brain, and uncoupling protein 2 (UCP2) has been demonstrated to regulate reactive oxygen species (ROS) production. However, it is unclear whether UCP2 is expressed in astrocytes, and whether it participates in the regulation of astrocytic functions. Here we show that UCP2 knockout exacerbated dopaminergic neuron loss in a murine model of 1,2,3,6-methyl-phenyl-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD), accompanied by overactivation of astrocytes. We further detected expression of UCP2 in primary cultures of mesencephalic astrocytes. UCP2 knockout increased intracellular ROS production and induced oxidative stress in response to l-methyl-4-phenylpyridinium (MPP(+)) treatment. Subsequently, UCP2 deficiency exacerbated endoplasmic reticulum (ER) stress, as evidenced by the upregulations of C/EBP homologous protein (CHOP), cleavage of caspase-12, and aggravated neuroinflammation via the activation of nod-like receptor protein 3 (NLRP3) inflammasomes in astrocytes. Collectively, our study indicates that UCP2 expressed in astrocytes modulates ER stress and neuroinflammation, and is crucial for the survival of dopaminergic neuron in the pathogenesis of PD. These findings gives us insights into the potential of UCP2 as a novel therapeutic avenue for PD treatment.

• Authors: Ming Lu, Xiu-Lan Sun, Chen Qiao, Yang Liu, Jian-Hua Ding, Gang Hu
• Journal: Neurobiology of aging (Neurobiol Aging) Vol. 35 Issue 2 Pg. 421-30 (Feb 2014) ISSN: 1558-1497 [Electronic] United States
• PMID: 24041971 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Carrier Proteins
• Glial Fibrillary Acidic Protein
• Inflammasomes
• Interleukin-1beta
• Ion Channels
• Mitochondrial Proteins
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• Reactive Oxygen Species
• Tumor Necrosis Factor-alpha
• UCP2 protein, human
• Ucp2 protein, mouse
• Uncoupling Protein 2
• L-Lactate Dehydrogenase
• Tyrosine 3-Monooxygenase

Topics

• Animals
• Astrocytes (cytology, metabolism, physiology)
• Carrier Proteins (physiology)
• Cells, Cultured
• Disease Models, Animal
• Endoplasmic Reticulum (metabolism)
• Endoplasmic Reticulum Stress
• Glial Fibrillary Acidic Protein (metabolism)
• Homeostasis
• Inflammasomes (genetics, physiology)
• Interleukin-1beta (metabolism)
• Ion Channels (deficiency)
• L-Lactate Dehydrogenase (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondria (metabolism)
• Mitochondrial Proteins (deficiency)
• NLR Family, Pyrin Domain-Containing 3 Protein
• Oxidation-Reduction
• Parkinson Disease (etiology, genetics)
• Parkinsonian Disorders
• Reactive Oxygen Species (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)
• Tyrosine 3-Monooxygenase (metabolism)
• Uncoupling Protein 2