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Antioxidant peroxiredoxin 6 protein rescues toxicity due to oxidative stress and cellular hypoxia in vitro, and attenuates prion-related pathology in vivo

Antioxidant peroxiredoxin 6 protein rescues toxicity due to oxidative stress and cellular hypoxia in vitro, and attenuates prion-related pathology in vivo
Antioxidant peroxiredoxin 6 protein rescues toxicity due to oxidative stress and cellular hypoxia in vitro, and attenuates prion-related pathology in vivo
Protein misfolding, mitochondrial dysfunction and oxidative stress are common pathomechanisms that underlie neurodegenerative diseases. In prion disease, central to these processes is the post-translational transformation of cellular prion protein (PrPc) to the aberrant conformationally altered isoform; PrPSc. This can trigger oxidative reactions and impair mitochondrial function by increasing levels of peroxynitrite, causing damage through formation of hydroxyl radicals or via nitration of tyrosine residues on proteins. The 6 member Peroxiredoxin (Prdx) family of redox proteins are thought to be critical protectors against oxidative stress via reduction of H2O2, hydroperoxides and peroxynitrite. In our in vitro studies cellular metabolism of SK-N-SH human neuroblastoma cells was significantly decreased in the presence of H2O2 (oxidative stressor) or CoCl2 (cellular hypoxia), but was rescued by treatment with exogenous Prdx6, suggesting that its protective action is in part mediated through a direct action. We also show that CoCl2-induced apoptosis was significantly decreased by treatment with exogenous Prdx6. We proposed a redox regulator role for Prdx6 in regulating and maintaining cellular homeostasis via its ability to control ROS levels that could otherwise accelerate the emergence of prion-related neuropathology. To confirm this, we established prion disease in mice with and without astrocyte-specific antioxidant protein Prdx6, and demonstrated that expression of Prdx6 protein in Prdx6 Tg ME7-animals reduced severity of the behavioural deficit, decreased neuropathology and increased survival time compared to Prdx6 KO ME7-animals. We conclude that antioxidant Prdx6 attenuates prion-related neuropathology, and propose that augmentation of endogenous Prdx6 protein represents an attractive adjunct therapeutic approach for neurodegenerative diseases.
neurodegeneration, prion, ME7, astrocytes, peroxiredoxin 6, antioxidant
0197-0186
1-14
Asuni, Ayodeji A.
b1412b1b-9794-4705-aada-aed5d3da038f
Guridi, Maitea
a9e5b9d5-8447-4124-a57c-f652e099a1c2
Sanchez, Sandrine
280cb177-57d0-4194-9742-24aaca487a42
Sadowski, Martin J.
8add36aa-b648-4378-91e3-94e85a19b977
Asuni, Ayodeji A.
b1412b1b-9794-4705-aada-aed5d3da038f
Guridi, Maitea
a9e5b9d5-8447-4124-a57c-f652e099a1c2
Sanchez, Sandrine
280cb177-57d0-4194-9742-24aaca487a42
Sadowski, Martin J.
8add36aa-b648-4378-91e3-94e85a19b977

Asuni, Ayodeji A., Guridi, Maitea, Sanchez, Sandrine and Sadowski, Martin J. (2015) Antioxidant peroxiredoxin 6 protein rescues toxicity due to oxidative stress and cellular hypoxia in vitro, and attenuates prion-related pathology in vivo. Neurochemistry International, 1-14. (PMID:26265052)

Record type: Article

Abstract

Protein misfolding, mitochondrial dysfunction and oxidative stress are common pathomechanisms that underlie neurodegenerative diseases. In prion disease, central to these processes is the post-translational transformation of cellular prion protein (PrPc) to the aberrant conformationally altered isoform; PrPSc. This can trigger oxidative reactions and impair mitochondrial function by increasing levels of peroxynitrite, causing damage through formation of hydroxyl radicals or via nitration of tyrosine residues on proteins. The 6 member Peroxiredoxin (Prdx) family of redox proteins are thought to be critical protectors against oxidative stress via reduction of H2O2, hydroperoxides and peroxynitrite. In our in vitro studies cellular metabolism of SK-N-SH human neuroblastoma cells was significantly decreased in the presence of H2O2 (oxidative stressor) or CoCl2 (cellular hypoxia), but was rescued by treatment with exogenous Prdx6, suggesting that its protective action is in part mediated through a direct action. We also show that CoCl2-induced apoptosis was significantly decreased by treatment with exogenous Prdx6. We proposed a redox regulator role for Prdx6 in regulating and maintaining cellular homeostasis via its ability to control ROS levels that could otherwise accelerate the emergence of prion-related neuropathology. To confirm this, we established prion disease in mice with and without astrocyte-specific antioxidant protein Prdx6, and demonstrated that expression of Prdx6 protein in Prdx6 Tg ME7-animals reduced severity of the behavioural deficit, decreased neuropathology and increased survival time compared to Prdx6 KO ME7-animals. We conclude that antioxidant Prdx6 attenuates prion-related neuropathology, and propose that augmentation of endogenous Prdx6 protein represents an attractive adjunct therapeutic approach for neurodegenerative diseases.

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Accepted/In Press date: 6 August 2015
e-pub ahead of print date: 8 August 2015
Keywords: neurodegeneration, prion, ME7, astrocytes, peroxiredoxin 6, antioxidant
Organisations: Centre for Biological Sciences

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Local EPrints ID: 383006
URI: https://eprints.soton.ac.uk/id/eprint/383006
ISSN: 0197-0186
PURE UUID: eeaeee22-c4b7-42ae-9283-ddbced23f7e9

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Date deposited: 21 Oct 2015 10:42
Last modified: 05 Oct 2017 00:43

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