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

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.

Peroxiredoxin 6 mediates protective function of astrocytes in Aβ proteostasis

“…Similar reactive behavior of PRDX6 is known from extra-CNS cell lineages where oxidative stress upregulates PRDX6 level and promotes its translocation from the cytosol to the cell membrane allowing access to peroxidized lipids as the metabolic substrate [43]. In our previous work, we experimentally proved that PRDX6 renders astrocytes resistant to oxidative damage [8]. Astrocytes cultured from Prdx6 overexpressing mice exhibit increased resistance to in vitro oxidative insult while astrocytes cultured from Prdx6 −/− mice, conversely show significantly reduced viability.…”

“…Here, we provide novel evidence that astrocytes play an active role in countering Aβ deposition, and identify PRDX6 protein as a key element of this process. PRDX6 is expressed by astrocytes but no other type of CNS glial cells [8,9]. As a prerequisite for this study, we determined that two-fold change in Prdx6 expression level does not affect astrocyte-resting state or alter soluble Aβ levels in AD Tg mice prior to appearance of Aβ plaques.…”

Copper stress response in yeast Rhodotorula mucilaginosa AN5 isolated from sea ice, Antarctic

“…Previous reports found that some antioxidant proteins were increased in yeast R. mucilaginosa RCL‐11 stressed by copper (Irazusta et al., ). Peroxiredoxin 6, a unique member of the ubiquitous peroxiredoxin family, was recruited to protect cells against oxidative stress via reduction of H 2 O 2 , hydroperoxides, and peroxynitrite, caused by heavy metal (Asuni, Guridi, Sanchez, & Sadowski, ). In this study, mitochondrial peroxiredoxin 6 (spot 2002 and 5109) were found significantly enhanced in yeast cells against the heavy metal stress.…”

Knockout Mouse Models for Peroxiredoxins

“…In ME7-infected prion disease models, Prdx6 deficiency worsens prion-related neuropathology [115]. These defects are caused by Prdx6 deficiency in astrocytes because PRDX6 is predominantly expressed in astrocytes rather than neurons in the brain [115].…”