Methionine oxidation accelerates the aggregation and enhances the neurotoxicity of the D178N variant of the human prion protein

Feng, Boya; Wang, Zonglin; Liu, Ting; Jin, Rui; Wang, Shaobo; Wang, Wei; Xiao, Gengfu; Zhou, Zheng

doi:10.1016/j.bbadis.2014.09.012

Cited by 11 publications

(7 citation statements)

References 78 publications

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“…Thus, we find it reasonable to assume that the binding of clusterin/apolipoprotein J to PrP and/or the PrP‐mediated packaging of clusterin/apolipoprotein J into exosomes is inhibited under oxidative stress, while binding and packaging of apolipoprotein E is not. In this context, it is noteworthy that reactive oxygen species change the confirmation of PrP (Feng et al, ; Requena et al, ; Younan et al, ). Thus, we consider it likely that oxidative and ischemic stress changes PrP conformation and that clusterin/apolipoprotein J does not bind to PrP in this conformation.…”

Section: Discussionmentioning

confidence: 99%

Improvement of neuronal cell survival by astrocyte‐derived exosomes under hypoxic and ischemic conditions depends on prion protein

Guitart

Loers

Buck

et al. 2016

Glia

154

107

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Prion protein (PrP) protects neural cells against oxidative stress, hypoxia, ischemia, and hypoglycemia. In the present study we confirm that cultured PrP-deficient neurons are more sensitive to oxidative stress than wild-type neurons and present the novel findings that wild-type, but not PrP-deficient astrocytes protect wild-type cerebellar neurons against oxidative stress and that exosomes released from stressed wild-type, but not from stressed PrP-deficient astrocytes reduce neuronal cell death induced by oxidative stress. We show that neuroprotection by exosomes of stressed astrocytes depends on exosomal PrP but not on neuronal PrP and that astrocyte-derived exosomal PrP enters into neurons, suggesting neuronal uptake of astrocyte-derived exosomes. Upon exposure of wild-type astrocytes to hypoxic or ischemic conditions PrP levels in exosomes were increased. By mass spectrometry and Western blot analysis, we detected increased levels of 37/67 kDa laminin receptor, apolipoprotein E and the ribosomal proteins S3 and P0, and decreased levels of clusterin/apolipoprotein J in exosomes from wild-type astrocytes exposed to oxygen/glucose deprivation relative to exosomes from astrocytes maintained under normoxic conditions. The levels of these proteins were not altered in exosomes from stressed PrP-deficient astrocytes relative to unstressed PrP-deficient astrocytes. These results indicate that PrP in astrocytes is a sensor for oxidative stress and mediates beneficial cellular responses, e.g. release of exosomes carrying PrP and other molecules, resulting in improved survival of neurons under hypoxic and ischemic conditions.

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Section: Discussionmentioning

confidence: 99%

Improvement of neuronal cell survival by astrocyte‐derived exosomes under hypoxic and ischemic conditions depends on prion protein

Guitart

Loers

Buck

et al. 2016

Glia

154

107

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“…Feng B found that the D178N variant was more susceptible to oxidation than the wild-type prion protein, and Met oxidation accelerates the aggregation and enhances the neurotoxicity of the D178N variant. 13 As we know, FFI is characterized by severe insomnia early in the disease course, and the prominent damage occurs in the thalamus and inferior olives.…”

Section: Discussionmentioning

confidence: 99%

Familial fatal insomnia with atypical clinical features in a patient with D178N mutation and homozygosity for Met at codon 129 of the prion protein gene

Sun

Lin

et al. 2015

Prion

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“…Interestingly, the D178N variant of PrP C was recently found to be more susceptible to methionine oxidation 45 . This PrP mutant has been linked with the inherited human prion disease fatal famililial insomnia (FFI) and methionine oxidation of D178N PrP C decreased its structural stability, enhanced its aggregation and increased neurotoxicity.…”

Section: Conflicting Evidence Linking Methionine Oxidation With Mammamentioning

confidence: 99%

Sup35 methionine oxidation is a trigger forde novo[PSI⁺] prion formation

Grant¹

2015

Prion

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The molecular basis by which fungal and mammalian prions arise spontaneously is poorly understood. A number of different environmental stress conditions are known to increase the frequency of yeast [PSI(+)] prion formation in agreement with the idea that conditions which cause protein misfolding may promote the conversion of normally soluble proteins to their amyloid forms. A recent study from our laboratory has shown that the de novo formation of the [PSI(+)] prion is significantly increased in yeast mutants lacking key antioxidants suggesting that endogenous reactive oxygen species are sufficient to promote prion formation. Our findings strongly implicate oxidative damage of Sup35 as an important trigger for the formation of the heritable [PSI(+)] prion in yeast. This review discusses the mechanisms by which the direct oxidation of Sup35 might lead to structural transitions favoring conversion to the transmissible amyloid-like form. This is analogous to various environmental factors which have been proposed to trigger misfolding of the mammalian prion protein (PrP(C)) into the aggregated scrapie form (PrP(Sc)).

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Methionine oxidation accelerates the aggregation and enhances the neurotoxicity of the D178N variant of the human prion protein

Cited by 11 publications

References 78 publications

Improvement of neuronal cell survival by astrocyte‐derived exosomes under hypoxic and ischemic conditions depends on prion protein

Improvement of neuronal cell survival by astrocyte‐derived exosomes under hypoxic and ischemic conditions depends on prion protein

Familial fatal insomnia with atypical clinical features in a patient with D178N mutation and homozygosity for Met at codon 129 of the prion protein gene

Sup35 methionine oxidation is a trigger forde novo[PSI⁺] prion formation

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Methionine oxidation accelerates the aggregation and enhances the neurotoxicity of the D178N variant of the human prion protein

Cited by 11 publications

References 78 publications

Improvement of neuronal cell survival by astrocyte‐derived exosomes under hypoxic and ischemic conditions depends on prion protein

Improvement of neuronal cell survival by astrocyte‐derived exosomes under hypoxic and ischemic conditions depends on prion protein

Familial fatal insomnia with atypical clinical features in a patient with D178N mutation and homozygosity for Met at codon 129 of the prion protein gene

Sup35 methionine oxidation is a trigger forde novo[PSI+] prion formation

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Sup35 methionine oxidation is a trigger forde novo[PSI⁺] prion formation