Protective effect against Parkinson's disease-related insults through the activation of XBP1

Sado, Megumi; Yamasaki, Yoshio; Iwanaga, Tomoyuki; Onaka, Yasushi; Ibuki, Tatsuki; Nishihara, Shigeki; Mizuguchi, Hiroshi; Momota, Hiroyuki; Kishibuchi, Ryuichi; Hashimoto, Tsuyoshi; Wada, Daisuke; Kitagawa, Hisashi; Watanabe, Takeshi

doi:10.1016/j.brainres.2008.11.104

Cited by 135 publications

(98 citation statements)

References 43 publications

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“…Based on studies performed in other cell types, the IRE1α-XBP1 pathway is usually considered to be a protective pathway of the UPR [35][36][37]. We observed that XBP1s overproduction protects rat fibroblasts against CPAinduced apoptosis.…”

Section: Discussionmentioning

confidence: 65%

Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis

et al. 2010

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Aims/hypothesis Pro-inflammatory cytokines involved in the pathogenesis of type 1 diabetes deplete endoplasmic reticulum (ER) Ca 2+ stores, leading to ER-stress and beta cell apoptosis. However, the cytokine-induced ER-stress response in beta cells is atypical and characterised by induction of the pro-apoptotic PKR-like ER kinase (PERK)-C/EBP homologous protein (CHOP) branch of the unfolded protein response, but defective X-box binding protein 1 (XBP1) splicing and activating transcription factor 6 activation. The purpose of this study was to overexpress spliced/active Xbp1 (XBP1s) to increase beta cell resistance to cytokine-induced ER-stress and apoptosis.Methods Xbp1s was overexpressed using adenoviruses and knocked down using small interference RNA in rat islet cells. In selected experiments, Xbp1 was also knocked down in FACS-purified rat beta cells and rat fibroblasts. Expression and production of XBP1s and key downstream genes and proteins was measured and beta cell function and viability were evaluated.

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Section: Discussionmentioning

confidence: 65%

Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis

et al. 2010

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“…More related to PD, XBP-1 mRNA splicing/activation by the ER-resident endonuclease IRE1 is triggered by ER stress (Yoshida et al, 2001). Interestingly, the activation of XBP-1 indeed protects against several toxin-associated PD-related phenotypes in dopaminergic cells (Sado et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

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

Duplan

Giaime

Viotti

et al. 2013

Journal of Cell Science

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SummaryParkin and DJ-1 are two multi-functional proteins linked to autosomal recessive early-onset Parkinson's disease (PD) that have been shown to functionally interact by as-yet-unknown mechanisms. We have delineated the mechanisms by which parkin controls DJ-1. Parkin modulates DJ-1 transcription and protein levels via a signaling cascade involving p53 and the endoplasmic reticulum (ER)-stressinduced active X-box-binding protein-1S (XBP-1S). Parkin triggers the transcriptional repression of p53 while p53 downregulates DJ-1 protein and mRNA expressions. We show that parkin-mediated control of DJ-1 is fully p53-dependent. Furthermore, we establish that p53 lowers the protein and mRNA levels of XBP-1S. Accordingly, we show that parkin ultimately upregulates XBP-1 levels. Subsequently, XBP-1S physically interacts with the DJ-1 promoter, thereby enhancing its promoter trans-activation, mRNA levels and protein expression. This data was corroborated by the examination of DJ-1 in both parkin-and p53-null mice brains. This transcriptional cascade is abolished by pathogenic parkin mutations and is independent of its ubiquitin-ligase activity. Our data establish a parkindependent ER-stress-associated modulation of DJ-1 and identifies p53 and XBP-1 as two major actors acting downstream of parkin in this signaling cascade in cells and in vivo. This work provides a mechanistic explanation for the increase in the unfolded protein response observed in PD pathology, i.e. that it is due to a defect in parkin-associated control of DJ-1.

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“…It has been reported by Silva et al [115], that deficiency of CHOP, a key ER stress marker, protects the neonatal striatum from neurotoxicant 6-hydroxydopamine. Reports also showed that forced expression of ER stress sensor proteins, ATF6 alpha [117] and spliced XBP1 [116], confines neurotoxininduced dopaminergic neuronal death [117]. These reports are indicative of the role of ER stress in the death and dysfunction of dopaminergic neurons exposed to neurotoxicant models of PD.…”

Section: Er Stress and Parkinson's Diseasementioning

confidence: 91%

Role of Endoplasmic Reticulum Stress and Unfolded Protein Responses in Health and Diseases

2015

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Endoplasmic reticulum (ER) is the site of protein synthesis, protein folding, maintainance of calcium homeostasis, synthesis of lipids and sterols. Genetic or environmental insults can alter its function generating ER stress. ER senses stress mainly by three stress sensor pathways, namely protein kinase R-like endoplasmic reticulum kinase-eukaryotic translation-initiation factor 2a, inositol-requiring enzyme 1a-X-box-binding protein 1 and activating transcription factor 6-CREBH, which induce unfolded protein responses (UPR) after the recognition of stress. Recent studies have demonstrated that ER stress and UPR signaling are involved in cancer, metabolic disorders, inflammatory diseases, osteoporosis and neurodegenerative diseases. However, the precise knowledge regarding involvement of ER stress in different disease processes is still debatable. Here we discuss the possible role of ER stress in various disorders on the basis of existing literature. An attempt has also been made to highlight the present knowledge of this field which may help to elucidate and conjure basic mechanisms and novel insights into disease processes which could assist in devising better future diagnostic and therapeutic strategies.

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Protective effect against Parkinson's disease-related insults through the activation of XBP1

Cited by 135 publications

References 43 publications

Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis

Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis

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

Role of Endoplasmic Reticulum Stress and Unfolded Protein Responses in Health and Diseases

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