Molecular Alterations in the Cerebellum of Sporadic Creutzfeldt–Jakob Disease Subtypes with DJ-1 as a Key Regulator of Oxidative Stress

Tahir, Waqas; Zafar, Saima; Llorens, Franc; Arora, Amandeep Singh; Thüne, Katrin; Schmitz, Matthias; Gotzmann, Nadine; Kruse, Niels; Mollenhauer, Brit; Torres, Juan María; Andréoletti, Olivier; Ferrer, Isidre; Zerr, Inga

doi:10.1007/s12035-016-0294-4

Cited by 12 publications

(19 citation statements)

References 103 publications

(130 reference statements)

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“…Both the MM1 and VV2 subtypes of sCJD had significantly increased the expression of phosphorylated NRF2 in comparison to the age-matched control brains. Additionally, this increase was also observed at the protein level in both the subtypes of sCJD as compared to the age-matched control brains (Tahir et al, 2018 ).…”

Section: Activation Of Nrf2 In Prion Diseasesmentioning

confidence: 79%

“…In other words, we can say that nearly 40% of the normal respiratory chain complexes were lost after treatment of prion-infected N2a cells with ferric ions (Yuan et al, 2013 ). Recently, Tahir et al ( 2018 ) demonstrated that the reactive sulfur species in combination with the ROS and the reactive nitrogen species, which lead to multiple toxic insults, were observed in the brain of sCJD patients. The build-up of oxidative stress beyond the tolerable level within the cell will deregulate many cellular functions, such as the deregulation of energy-dependent metabolic pathways (Dringen et al, 2000 ), the impairment of energy-producing mitochondrial network (Gandhi and Abramov, 2012 ), the impairment of signal transduction (Apel and Hirt, 2004 ), the activation of the cell death pathways (Salganik, 2001 ), and the misfolding/aggregation of the pathogenic proteins (Bruijn et al, 1998 ; Valentine and Hart, 2003 ).…”

Section: Oxidative Stress In Prion Diseasesmentioning

confidence: 99%

“…The ubiquitin-proteasomes system is responsible for the continuous ubiquitination and degradation of NRF2 in the cytoplasm. Tahir et al ( 2018 ) recently reported a significant decrease in the expression of degraded NRF2 in the two subtypes of sCJD, termed as MM1 and VV2, in comparison to the similar age control brains. The release of transcription factor NRF2 from Keap1 leads to its phosphorylation.…”

Section: Activation Of Nrf2 In Prion Diseasesmentioning

confidence: 99%

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p62-Keap1-NRF2-ARE Pathway: A Contentious Player for Selective Targeting of Autophagy, Oxidative Stress and Mitochondrial Dysfunction in Prion Diseases

Shah

Zhao

Hussain

et al. 2018

Front. Mol. Neurosci.

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Prion diseases are a group of fatal and debilitating neurodegenerative diseases affecting humans and animal species. The conversion of a non-pathogenic normal cellular protein (PrPc) into an abnormal infectious, protease-resistant, pathogenic form prion protein scrapie (PrPSc), is considered the etiology of these diseases. PrPSc accumulates in the affected individual’s brain in the form of extracellular plaques. The molecular pathways leading to neuronal cell death in prion diseases are still unclear. The free radical damage, oxidative stress and mitochondrial dysfunction play a key role in the pathogenesis of the various neurodegenerative disorders including prion diseases. The brain is very sensitive to changes in the redox status. It has been demonstrated that PrPc behaves as an antioxidant, while the neurotoxic prion peptide PrPSc increases hydrogen peroxide toxicity in the neuronal cultures leading to mitochondrial dysfunction and cell death. The nuclear factor erythroid 2-related factor 2 (NRF2) is an oxidative responsive pathway and a guardian of lifespan, which protect the cells from free radical stress-mediated cell death. The reduced glutathione, a major small molecule antioxidant present in all mammalian cells, and produced by several downstream target genes of NRF2, counterbalances the mitochondrial reactive oxygen species (ROS) production. In recent years, it has emerged that the ubiquitin-binding protein, p62-mediated induction of autophagy, is crucial for NRF2 activation and elimination of mitochondrial dysfunction and oxidative stress. The current review article, focuses on the role of NRF2 pathway in prion diseases to mitigate the disease progression.

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Section: Activation Of Nrf2 In Prion Diseasesmentioning

confidence: 79%

Section: Oxidative Stress In Prion Diseasesmentioning

confidence: 99%

Section: Activation Of Nrf2 In Prion Diseasesmentioning

confidence: 99%

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p62-Keap1-NRF2-ARE Pathway: A Contentious Player for Selective Targeting of Autophagy, Oxidative Stress and Mitochondrial Dysfunction in Prion Diseases

Shah

Zhao

Hussain

et al. 2018

Front. Mol. Neurosci.

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“…From the molecular perspective, human cerebellum was less investigated; however, a number of dedicated proteomics studies, employing specific high‐performance analytical techniques, such as mono‐ and two‐dimensional gel electrophoresis, capillary electrophoresis, and mass spectrometry (MS) with either matrix assisted laser desorption/ionization (MALDI), MALDI‐imaging, or electrospray ionization (ESI) have demonstrated a correlation between the pattern of the cerebellum proteome and some of the pathologies affecting it, such as AD, neurodevelopmental and degenerative disorders, and neoplastic transformations occurring at this level…”

Section: Introductionmentioning

confidence: 99%

Orbitrap mass spectrometry for monitoring the ganglioside pattern in human cerebellum development and aging

et al. 2020

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We have developed here a superior approach based on high-resolution (HR) mass spectrometry (MS) for monitoring the changes occurring with development and aging in the composition and structure of cerebellar gangliosidome. The experiments were focused on the comparative screening and structural analysis of gangliosides expressed in fetal and aged cerebellum by Orbitrap MS with nanoelectrospray ionization (nanoESI) in the negative ion mode. The employed ultrahigh-resolution MS platform allowed the discrimination, without the need of previous separation, of 159 ions corresponding to 120 distinct species in the native ganglioside mixtures from fetal and aged cerebellar biopsies, many more than detected before, when MS platforms of lower resolution were employed. A number of gangliosides, in particular polysialylated belonging to GT, GQ, GP, and GS classes, modified by O-fucosylation, O-acetylation, or CH 3 COO − were discovered here, for the first time in human cerebellum. These components, found differently expressed in fetal and aged tissues, indicated that the ganglioside profile in cerebellum is development stage-and agespecific. Following the fragmentation analysis by high-energy collision-induced dissociation (HCD) tandem MS (MS/MS), we have also observed that the intimate structure of certain compounds has not changed during the development and aging of the brain, an aspect which could open new directions in the investigation of ganglioside biomarkers in cerebellar tissue.

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“…In addition, DJ-1 expression has been reported to increase in cancer cells; this increase is important for cancer pathology (Kawate et al, 2017;Kim et al, 2005). Increased expression of DJ-1 within the brain cells has also been observed in several neurodegenerative diseases, such as Parkinson's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Huntington's disease, and Alzheimer's disease (Choi et al, 2006;Lev et al, 2009;Saito et al, 2014;Sajjad et al, 2014;Tahir et al, 2018). Extracellular DJ-1 may affect the pathologies of cancer and neurodegenerative diseases and could also be a therapeutic target against inflammatory diseases and tissue injuries.…”

Section: Discussionmentioning

confidence: 98%

Extracellular DJ-1 induces sterile inflammation in the ischemic brain

Nakamura

Sakai

Tsuyama

et al. 2020

Preprint

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Inflammation is implicated in the onset and progression of various diseases, including cerebral pathologies. Here we report that DJ-1, which plays a role within cells as an antioxidant protein, functions as a damage-associated molecular pattern (DAMP), and triggers inflammation if released from dead cells into the extracellular space. We first found that recombinant DJ-1 protein induces the production of various inflammatory cytokines in bone marrow-derived macrophages (BMMs). We further identified a unique peptide sequence in the αG and αH helices of DJ-1 that activates Toll-like receptor 2 (TLR2) and TLR4. In the ischemic brain, DJ-1 is released into the extracellular space from necrotic neurons within 24 hours after stroke onset and makes direct contact with the surfaces of infiltrating myeloid cells. Administration of an antibody against DJ-1 suppresses the expression of inflammatory cytokines in infiltrating immune cells and attenuates ischemic neuronal damage. Our results demonstrate a previously unknown function of DJ-1 as a DAMP and suggest that extracellular DJ-1 could be a therapeutic target to prevent inflammation in tissue injuries and neurodegenerative diseases.Significance statementDJ-1 has been thoroughly investigated as a cytoprotective antioxidant protein in neurons. However, here we demonstrate that extracellularly released DJ-1 triggers neurotoxic inflammation after ischemic stroke. Intracellular DJ-1 increases in response to oxidative stress in ischemic neurons, but if ischemic stresses result in necrotic cell death, DJ-1 is released extracellularly. Released DJ-1 interacts with TLR2 and TLR4 on the surface of infiltrating myeloid cells and triggers post-ischemic inflammation, leading to the exacerbated pathologies of ischemic stroke. Thus, extracellular DJ-1 is a previously unknown inflammatogenic DAMP, and may be a putative target for therapeutic intervention to prevent progression of inflammatory and neurodegenerative diseases.

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Molecular Alterations in the Cerebellum of Sporadic Creutzfeldt–Jakob Disease Subtypes with DJ-1 as a Key Regulator of Oxidative Stress

Cited by 12 publications

References 103 publications

p62-Keap1-NRF2-ARE Pathway: A Contentious Player for Selective Targeting of Autophagy, Oxidative Stress and Mitochondrial Dysfunction in Prion Diseases

p62-Keap1-NRF2-ARE Pathway: A Contentious Player for Selective Targeting of Autophagy, Oxidative Stress and Mitochondrial Dysfunction in Prion Diseases

Orbitrap mass spectrometry for monitoring the ganglioside pattern in human cerebellum development and aging

Extracellular DJ-1 induces sterile inflammation in the ischemic brain

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