Nrf2-encoding NFE2L2 haplotypes influence disease progression but not risk in Alzheimer's disease and age-related cataract

Otter, Malin von; Landgren, Sara; Nilsson, Staffan; Zetterberg, Madeleine; Celojevic, Dragana; Bergström, Petra; Minthon, Lennart; Bogdanović, Nenad; Andreasen, Niels; Gustafson, Deborah; Skoog, Ingmar; Wallin, Anders; Tasa, Gunnar; Blennow, Kaj; Nilsson, Michael; Hammarsten, Ola; Zetterberg, Henrik

doi:10.1016/j.mad.2009.12.007

Cited by 82 publications

(65 citation statements)

References 50 publications

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“…Nrf2 activation, either by tert-butylhydroquinone treatment or viral Nrf2 gene transfection, has been shown to be protective in an APP/PS1 transgenic mouse model (Kanninen et al 2008(Kanninen et al , 2009, as well as in neuronal cells exposed to exogenous Ab (Wruck et al 2008). Interestingly, a polymorphism in the human Nrf2 gene, NFE2L2, has recently been associated with earlier AD onset (Von Otter et al 2010).…”

Section: Resultsmentioning

confidence: 99%

Genetic Mechanisms of Coffee Extract Protection in aCaenorhabditis elegansModel of β-Amyloid Peptide Toxicity

2010

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Epidemiological studies have reported that coffee and/or caffeine consumption may reduce Alzheimer's disease (AD) risk. We found that coffee extracts can similarly protect against b-amyloid peptide (Ab) toxicity in a transgenic Caenorhabditis elegans Alzheimer's disease model. The primary protective component(s) in this model is not caffeine, although caffeine by itself can show moderate protection. Coffee exposure did not decrease Ab transgene expression and did not need to be present during Ab induction to convey protection, suggesting that coffee exposure protection might act by activating a protective pathway. By screening the effects of coffee on a series of transgenic C. elegans stress reporter strains, we identified activation of the skn-1 (Nrf2 in mammals) transcription factor as a potential mechanism of coffee extract protection. Inactivation of skn-1 genetically or by RNAi strongly blocked the protective effects of coffee extract, indicating that activation of the skn-1 pathway was the primary mechanism of coffee protection. Coffee also protected against toxicity resulting from an aggregating form of green fluorescent protein (GFP) in a skn-1-dependent manner. These results suggest that the reported protective effects of coffee in multiple neurodegenerative diseases may result from a general activation of the Nrf2 phase II detoxification pathway.

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Section: Resultsmentioning

confidence: 99%

Genetic Mechanisms of Coffee Extract Protection in aCaenorhabditis elegansModel of β-Amyloid Peptide Toxicity

2010

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“…Variations in its promoter have been shown to affect NRF2 protein expression and to be associated with various diseases, including neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease (53,54). Given the central role of NRF2 and KEAP1 in the antioxidant pathway, and the multitude of evidence for oxidative stress in ALS, it is no surprise that multiple laboratories have investigated the association between NRF2 and KEAP1 haplotypes and ALS.…”

Section: Discussionmentioning

confidence: 99%

RBM45 Modulates the Antioxidant Response in Amyotrophic Lateral Sclerosis through Interactions with KEAP1

Bakkar

Kousari

Kovalik

et al. 2015

Molecular and Cellular Biology

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons. Various factors contribute to the disease, including RNA binding protein dysregulation and oxidative stress, but their exact role in pathogenic mechanisms remains unclear. We have recently linked another RNA binding protein, RBM45, to ALS via increased levels of protein in the cerebrospinal fluid of ALS patients and its localization to cytoplasmic inclusions in ALS motor neurons. Here we show RBM45 nuclear exit in ALS spinal cord motor neurons compared to controls, a phenotype recapitulated in vitro in motor neurons treated with oxidative stressors. We find that RBM45 binds and stabilizes KEAP1, the inhibitor of the antioxidant response transcription factor NRF2. ALS lumbar spinal cord lysates similarly show increased cytoplasmic binding of KEAP1 and RBM45. Binding of RBM45 to KEAP1 impedes the protective antioxidant response, thus contributing to oxidative stress-induced cellular toxicity. Our findings thus describe a novel link between a mislocalized RNA binding protein implicated in ALS (RBM45) and dysregulation of the neuroprotective antioxidant response seen in the disease.A myotrophic lateral sclerosis (ALS) is a fatal idiopathic adultonset neurodegenerative disease characterized by a loss of motor neurons in the brain, brain stem, and spinal cord, with consequent atrophy of associated muscles (1, 2). Incidence rates are 1 to 3 cases per 100,000 individuals per year. Pathogenic mechanisms underlying the disease are not fully understood. Approximately 5 to 10% of all ALS cases are familial (3), with the remaining cases being termed sporadic, contributing to the clinical heterogeneity within the patient population. Nevertheless, typical hallmarks of ALS include neuronal atrophy, mitochondrial dysfunction, excitotoxicity, oxidative stress, and ubiquitinated cellular inclusions (4, 5). A growing number of genes with diverse functions have been implicated in the disease etiology. Mutations in a number of RNA binding proteins have been linked to ALS, including TAR DNA binding protein 43 (TDP-43) and Fused in Sarcoma (FUS) (6). Mutations in these genes result in reduced levels in the nucleus and their accumulation in cytoplasmic ubiquitin-positive inclusions (7). Both TDP-43 and FUS possess prion-like domains and relocate to cytoplasmic stress granules under stress conditions, suggesting potential pathology commonalities (8). Genetic alterations in these and other RNA binding proteins link RNA metabolism to the pathobiology of ALS.Recently, we linked another RNA binding protein, RBM45, to ALS using a proteomic screen of cerebrospinal fluid (CSF) from ALS and control subjects (9). RBM45, also known as Drb1, was first identified as a novel RNA binding protein that functions in neural development (10). RBM45 possesses three RNA recognition motifs (RRMs) as well as a C-terminal nuclear localization sequence (10). By using a large liquid chromatography-tandem mass spectrometry (LC-MS/MS) unbia...

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“…Interestingly, this haplotype was associated with a 4-year delay in onset of ALS (Bergstrom et al, 2014), but another study did not find a clear association (LoGerfo et al, 2014). Regarding AD, one haplotype allele was associated with 2-year earlier age onset of AD, suggesting that variants of the NFE2L2 gene may affect AD progression (von Otter et al, 2010b). Genetic association of NFE2L2 with PD has been analyzed in more detail.…”

Section: G Nuclear Factor (Erythroid-derived 2)-like 2 In Neurodegenmentioning

confidence: 99%

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

et al. 2018

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Nrf2-encoding NFE2L2 haplotypes influence disease progression but not risk in Alzheimer's disease and age-related cataract

Cited by 82 publications

References 50 publications

Genetic Mechanisms of Coffee Extract Protection in aCaenorhabditis elegansModel of β-Amyloid Peptide Toxicity

Genetic Mechanisms of Coffee Extract Protection in aCaenorhabditis elegansModel of β-Amyloid Peptide Toxicity

RBM45 Modulates the Antioxidant Response in Amyotrophic Lateral Sclerosis through Interactions with KEAP1

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

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