Activation of apoptosis signal regulating kinase 1 (ASK1) and translocation of death‐associated protein, Daxx, in substantia nigra pars compacta in a mouse model of Parkinson's disease: protection by α‐lipoic acid

Abstract

Parkinson's disease (PD), a neurodegenerative disorder, causes severe motor impairment due to loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). MPTP, a neurotoxin that causes dopaminergic cell loss in mice, was used in an animal model to study the pathogenic mechanisms leading to neurodegeneration. We observed the activation of apoptosis signal regulating kinase (ASK1, MAPKKK) and phosphorylation of its downstream targets MKK4 and JNK, 12 h after administration of a single dose of MPTP. Further, Daxx, the death-associated protein, translocated to the cytosol selectively in SNpc neurons seemingly due to MPTP mediated down-regulation of DJ-1, the redox-sensitive protein that binds Daxx in the nucleus. Coadministration of alpha-lipoic acid (ALA), a thiol antioxidant, abolished the activation of ASK1 and phosphorylation of downstream kinases, MKK4, and JNK and prevented the down-regulation of DJ-1 and translocation of Daxx to the cytosol seen after MPTP. ALA also attenuated dopaminergic cell loss in SNpc seen after subchronic MPTP treatment. Our studies demonstrate for the first time that MPTP triggers death signaling pathway by activating ASK1 and translocating Daxx, in vivo, in dopaminergic neurons in SNpc of mice and thiol antioxidants, such as ALA terminate this cascade and afford neuroprotection.

Oxidizable Residues Mediating Protein Stability and Cytoprotective Interaction of DJ-1 with Apoptosis Signal-regulating Kinase 1

“…6). [wt]DJ-1 abolished nuclear export of FLAG/Daxx under these conditions (Fig. 6), consistent with previous reports in cell culture and mouse models (24,39). In contrast, the PD-associated mutant [M26I]DJ-1 lost nuclear retention of FLAG/Daxx, leading to highly significant nuclear export of Daxx into the cytosol, where it is known to promote cell death (40).…”

DJ-1 Could Predict Worse Prognosis in Esophageal Squamous Cell Carcinoma

“…Previously, DJ-1 has been shown to protect cells from apoptosis through sequestering Daxx in the nucleus, thereby inhibiting Daxx-induced apoptosis (6,22). In the present study, we found that nuclear, but not cytoplasmic, expression of DJ-1 was positively associated with nuclear expression of Daxx, suggesting that DJ-1 might promote ESCC progression through the same mechanism.…”

“…Recently, DJ-1-mediated apoptosis has been shown to be attributed by its ability to interact with Daxx, the death-associated protein, and retain Daxx in nuclear localization (6,22). In this study, we found that nuclear DJ-1 (r = 0.296; P = 0.01) but not cytoplasmic DJ-1 (r = 0.079; P = 0.501) or combined DJ-1 score (r = 0.244; P = 0.057) was significantly associated with nuclear expression of Daxx (Fig.…”

Erythropoietin: Elucidating new cellular targets that broaden therapeutic strategies

“…Apoptotic induced oxidative stress in conjunction with processes of mitochondrial dysfunction can contribute to a variety of disease states such as diabetes, ischemia, general cognitive loss, Alzheimer's disease, and trauma (Chong et al, 2005e;f;Harris et al, 2007;Leuner et al, 2007;Okouchi et al, 2007). Oxidative stress can lead to apoptosis in a variety of cell types that involve neurons, ECs, cardiomyocytes, and smooth muscle cells through multiple cellular pathways Harris et al, 2007;Kang et al, 2003b;Karunakaran et al, 2007;Verdaguer et al, 2007).…”