Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress

Abstract

Loss of parkin function is responsible for the majority of autosomal recessive parkinsonism. Here, we show that parkin is not only a stress-protective, but also a stress-inducible protein. Both mitochondrial and endoplasmic reticulum (ER) stress induce an increase in parkin-specific mRNA and protein levels. The stress-induced upregulation of parkin is mediated by ATF4, a transcription factor of the unfolded protein response (UPR) that binds to a specific CREB/ATF site within the parkin promoter. Interestingly, c-Jun can bind to the same site, but acts as a transcriptional repressor of parkin gene expression. We also present evidence that mitochondrial damage can induce ER stress, leading to the activation of the UPR, and thereby to an upregulation of parkin expression. Vice versa, ER stress results in mitochondrial damage, which can be prevented by parkin. Notably, the activity of parkin to protect cells from stress-induced cell death is independent of the proteasome, indicating that proteasomal degradation of parkin substrates cannot explain the cytoprotective activity of parkin. Our study supports the notion that parkin has a role in the interorganellar crosstalk between the ER and mitochondria to promote cell survival under stress, suggesting that both ER and mitochondrial stress can contribute to the pathogenesis of Parkinson's disease.

ER-stress-associated functional link between Parkin and DJ-1 via a transcriptional cascade involving the tumor suppressor p53 and the spliced X-box binding protein XBP-1

“…Phopho-PERK then phosphorylates the initiation factor peIF2a that increases the transcription of ATF4 (Zhang and Kaufman, 2006). Interestingly, parkin was recently shown to be transcriptionally modulated by ATF4 (Bouman et al, 2011). Therefore, overall, our work identifies a cellular response to ERstress implying a transcriptional cascade by which parkin-mediated p53-dependent activation of XBP-1 could prevent ER-stressmediated cell death by increasing DJ-1 levels.…”

“…Thus, parkin-associated control of the UPR could be linked to its enzymatic properties and it was proposed that its defect could account for selective dopaminergic neurons death. However, it is noteworthy that it was recently documented that parkin-associated protection against ER-stress-induced cell death could be independent of the proteasomal machinery, indicating that parkin-related neuroprotection against ER-stress could not necessarily require its ubiquitin-ligase activity (Bouman et al, 2011). In this context, it is interesting that we recently documented an additional parkinassociated function as a transcription factor (da Costa et al, 2009).…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…One of contributing factors for PD development is loss of the E3 ubiquitin ligase Parkin in dopaminergic neurons. The expression of Parkin is induced by ER stress through direct binding of ATF4 to the promoter region of the Parkin gene (Bouman et al 2011). Given the protective role of Parkin, these results suggest that ATF4 promotes dopaminergic cell survival during PD pathogenesis.…”

Genesis of ER stress in Huntington’s Disease

“…Mutations in Parkin, a ubiquitin ligase, cause another familial form of PD, resulting in an impairment of its activity [150]. Parkin localizes to the ER and is upregulated by the UPR [151]. The levels of phosphorylated PERK and eIF2α were also found elevated in brain samples of patients with sporadic PD [148], whereas Sigma-1R levels decreased [136] Increased levels of UPR markers were also found in brain samples from patients with amyotrophic lateral sclerosis (ALS) [152].…”