N-homocysteinylation of ovine prion protein induces amyloid-like transformation

Stroylova, Yulia Yu.; Chobert, Jean‐Marc; Muronetz, Vladimir I.; Jakubowski, Hieronim; Haertlé, Thomas

doi:10.1016/j.abb.2012.06.008

Cited by 19 publications

(15 citation statements)

References 45 publications

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“…Multiple factors, including genetic variation, physicochemical environment, and posttranslational modifications (such as glycation) [346] determine the propensity of PrP C to form aggregates. Taken together, these findings show that N-homocysteinylation accelerates amyloid-like transformation of PrP C [347]. Incubation of ovine PrP C with Hcy-thiolactone leads to Nhomocysteinylation of the residues Lys197 and Lys207 and the formation of prion multimers, detected on nonreducing SDS-PAGE gels.…”

Section: N-hcy-prionmentioning

confidence: 53%

“…The form of disease is determined by two prion types, which differ in their stabilities against denaturing agents, have different proteinase K cleavage sites, and form different prion aggregate deposits [345]. A recent study suggests that N-homocysteinylation contributes to the conversion of PrP C to PrP Sc [347]. A recent study suggests that N-homocysteinylation contributes to the conversion of PrP C to PrP Sc [347].…”

Section: N-hcy-prionmentioning

confidence: 99%

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Homocysteine in Protein Structure/Function and Human Disease

Jakubowski¹

2013

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Section: N-hcy-prionmentioning

confidence: 53%

Section: N-hcy-prionmentioning

confidence: 99%

Homocysteine in Protein Structure/Function and Human Disease

Jakubowski¹

2013

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“…High concentrations of Hcy have been shown to exert harmful effects on neurons through reversible mechanisms such as oxidative stress, endoplasmic reticulum stress, excitotoxicity and epigenomic mechanisms . Hcy can produce cumulative effects by two mechanisms demonstrated in various models . One is the reversible S‐homocysteinylation of protein cysteine residues, and the other is the more stable N‐homocysteinylation of lysine residues by Hcy–thiolactone (HcyTh), a compound produced by methionine tRNAsynthetase (MARS) .…”

Section: Introductionmentioning

confidence: 99%

N‐homocysteinylation of tau and MAP1 is increased in autopsy specimens of Alzheimer's disease and vascular dementia

Bossenmeyer‐Pourié

Smith

Lehmann

et al. 2019

The Journal of Pathology

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The pathomechanisms that associate a deficit in folate and/or vitamin B12 and the subsequent hyperhomocysteinemia with pathological brain ageing are unclear. We investigated the homocysteinylation of microtubule‐associated proteins (MAPs) in brains of patients with Alzheimer's disease or vascular dementia, and in rats depleted in folate and vitamin B12, Cd320 KO mice with selective B12 brain deficiency and H19‐7 neuroprogenitors lacking folate. Compared with controls, N‐homocysteinylated tau and MAP1 were increased and accumulated in protein aggregates and tangles in the cortex, hippocampus and cerebellum of patients and animals. N‐homocysteinylation dissociated tau and MAPs from β‐tubulin, and MS analysis showed that it targets lysine residues critical for their binding to β‐tubulin. N‐homocysteinylation increased in rats exposed to vitamin B12 and folate deficit during gestation and lactation and remained significantly higher when they became 450 days‐old, despite returning to normal diet at weaning, compared with controls. It was correlated with plasma homocysteine (Hcy) and brain expression of methionine tRNAsynthetase (MARS), the enzyme required for the synthesis of Hcy–thiolactone, the substrate of N‐homocysteinylation. Experimental inactivation of MARS prevented the N‐homocysteinylation of tau and MAP1, and the dissociation of tau and MAP1 from β‐tubulin and PSD95 in cultured neuroprogenitors. In conclusion, increased N‐homocysteinylation of tau and MAP1 is a mechanism of brain ageing that depends on Hcy concentration and expression of MARS enzyme. Its irreversibility and cumulative occurrence throughout life may explain why B12 and folate supplementation of the elderly has limited effects, if any, to prevent pathological brain ageing and cognitive decline. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…Once entering an acceptor cell, pathogenic polypeptides recruit intracellular proteins, homologic, or non-homologic, to prionize them. Prionization effect has been demonstrated for tau, α-synuclein, SOD1, TDP-43, and polyglutamine, however, whether this mechanism involves the mobilizing of monomers of misfolded proteins and through the formation of various forms of aggregates (as happens in case of “real” prions) needs further investigation (Stroylova et al, 2012; Bose and Cho, 2017). Since molecular chaperones have been convincingly shown to defend those cells in which the pathogenic oligomers and aggregates are initially formed, as well as cells secondarily infected by prion-like pathogens, we suggest that the activation of molecular chaperones is a potent instrument for coping with transmitting proteotoxic pathologies.…”

Section: Role Of Chaperones At the Final Stage Of Prionizationmentioning

confidence: 99%

Possible Function of Molecular Chaperones in Diseases Caused by Propagating Amyloid Aggregates

et al. 2017

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The vast majority of neurodegenerative pathologies stem from the formation of toxic oligomers and aggregates composed of wrongly folded proteins. These protein complexes can be released from pathogenic cells and enthralled by other cells, causing the formation of new aggregates in a prion-like manner. By this mechanism, migrating complexes can transmit a disorder to distant regions of the brain and promote gradually transmitting degenerative processes. Molecular chaperones can counteract the toxicity of misfolded proteins. In this review, we discuss recent data on the possible cytoprotective functions of chaperones in horizontally transmitting neurological disorders.

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N-homocysteinylation of ovine prion protein induces amyloid-like transformation

Cited by 19 publications

References 45 publications

Homocysteine in Protein Structure/Function and Human Disease

Homocysteine in Protein Structure/Function and Human Disease

N‐homocysteinylation of tau and MAP1 is increased in autopsy specimens of Alzheimer's disease and vascular dementia

Possible Function of Molecular Chaperones in Diseases Caused by Propagating Amyloid Aggregates

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