Peroxiredoxin-2 Protects against 6-Hydroxydopamine-Induced Dopaminergic Neurodegeneration via Attenuation of the Apoptosis Signal-Regulating Kinase (ASK1) Signaling Cascade

Abstract

The peroxiredoxin (PRX) family of antioxidant enzymes helps maintain the intracellular reducing milieu and suppresses apoptosis in non-neuronal cells. However, whether PRX can inhibit neuronal apoptosis through specific signaling mechanisms remains poorly understood. Induction of PRX2, the most abundant neuronal PRX, occurs in Parkinson's disease (PD) patient brains, but its functional impact is unclear. In the present study, we used the dopaminergic (DA) toxin 6-hydroxydopamine (6-OHDA) to model PD and explore the protective effect and mechanisms of PRX on DA neurons. Of the 2-cysteine PRXs that were tested in MN9D DA neurons, endogenous PRX2 was most beneficial to cell survival. Lentivirus-mediated PRX2 over-expression conferred marked in vitro and in vivo neuroprotection against 6-OHDA toxicity in DA neurons, and preserved motor functions involving the dopamine system in mouse. In addition to its role as an antioxidant enzyme, PRX2 exhibited anti-apoptotic effects in DA neurons via suppression of ASK1-dependent activation of the JNK/c-Jun and p38 pro-death pathways, which are also activated in DA neurons of post-mortem PD brains. PRX2 inhibited 6-OHDA-induced ASK1 activation by modulating the redox status of the endogenous ASK1 inhibitor thioredoxin (Trx). PRX2 over-expression maintained Trx in a reduced state by inhibiting the cysteine thiol-disulfide exchange, thereby preventing its dissociation from ASK1. This study describes a previously undefined mechanism by which redox-sensitive molecules signal via apoptotic pathways in response to PD-relevant toxic stress in DA neurons. Our results also suggest that PRX2 and ASK1 may be potential targets for neuroprotective intervention in PD.

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

“…Peptidyl‐prolyl cis/trans isomerase A regulates protein folding at proline residues and affects tau aggregation (Blair et al ., 2015). Peroxiredoxins 1 and 2 protect against huntingtin neurotoxicity (Pitts et al ., 2012) and dopaminergic neurodegeneration (Hu et al ., 2011). Phosphoglycerate mutase activity in brain decreases with aging and especially with AD (Meier‐Ruge et al ., 1984), perhaps explained by its AD‐specific accumulation in aggregates.…”

The Peptidyl-prolyl Isomerase Pin1 Up-regulation and Proapoptotic Function in Dopaminergic Neurons

“…For the cell culture model, we adopted widely used MN9D mouse dopaminergic neuronal cells because of the amenability of the cells for biochemical studies relevant to dopaminergic neurodegeneration (35,36). First, we sought to understand changes to the Pin1 message and protein levels upon treatment with the parkinsonian toxicant MPP ϩ .…”

ASK1 and Its Role in Neurodegenerative Diseases

“…Specifically, the cysteine residue at position 250 (Cys250) in ASK1 was identified as an essential residue for JNK activation in response to H 2 O 2 -induced stress. Recently, redox sensitive molecules such as the Parkinson's associated protein DJ-1 (a.k.a PARK7) and Peroxiredoxin-2 have also been shown to attenuate ASK1 activity in response to toxic stress in dopaminergic neurons [27][28][29]. Interestingly, mutation analyses demonstrated, that the ER stress-inducing agent thapsigargin, while inducing ASK1 activation (as determined by Thr838 phosphorylation) was observed to be independent of Cys250 [25].…”

“…Beside ROS-induced ASK1 activation, Aβ, a toxic cleavage product of APP, was also demonstrated to activate ASK1 and subsequently JNK [68]. Whereas primary neuronal cultures derived from E14.5 ASK +/+ mice demonstrated an 80% reduction in cell viability after exposure to Aβ [25][26][27][28][29][30][31][32][33][34][35] , the survival in ASK -/-derived neurons treated with Aβ [25][26][27][28][29][30][31][32][33][34][35] was significantly elevated (only 30% reduction in viability). Furthermore, postmortem analysis of AD patient brains compared with age-matched controls revealed strong expression of the downstream ASK1 substrate MKK6 [69].…”

“…Co-administration of MPTP with α-lipoic acid, a thiol antioxidant inhibited the activation of ASK1 and subsequent activation of its downstream targets [80]. Recently, peroxiredoxin2 (PRX2), an antioxidant enzyme, was demonstrated to protect against 6-OHDA induced neurotoxicity both in vitro and in vivo [27]. The proposed mechanism of inhibition was through blockade of ASK1 activation and its downstream JNK/p38 signaling pathway.…”