Manganese-induced changes of the biochemical characteristics of the recombinant wild-type and mutant PrPs

Li, Xiaoli; Dong, Chenfang; Wang, Guirong; Zhou, Rong; Shi, Qi; Tian, Chan; Gao, Chen; Mei, Guo-yong; Chen, Cao; Xu, Kailin; Han, Jun; Dong, Xiao‐Ping

doi:10.1007/s00430-009-0120-y

Cited by 12 publications

(6 citation statements)

References 29 publications

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“…In accordance with previous data (29), the PK resistance of PG0 and PG12 was much stronger than PG5 in the present study. After redox, the PK resistance of oxidized PG5 and PG12 was markedly increased, whereas that of oxidized PG0 was only slightly increased.…”

Section: Discussionsupporting

confidence: 94%

Redox induces diverse effects on recombinant human wild-type PrP and mutated PrP with inserted or deleted octarepeats

et al. 2018

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Normal prion protein (PrP) contains two cysteines at amino acids 179 and 214, which may form intra‑ and interpeptide disulfide bonds. To determine the possible effects of this disulfide bridge on the biochemical features of PrP, prokaryotic recombinant human wild‑type PrP (PG5), and mutated PrPs with seven extra octarepeats (PG12) or with all five octarepeats removed (PG0), were subjected to redox in vitro. Sedimentation assays revealed a large portion of aggregation in redox‑treated PG5, but not in PG0 and PG12. Circular dichroism analysis detected increased β‑sheet and decreased α‑helix in PG5 subjected to redox, increased random‑coil and decreased β‑sheet in PG0, and increased random‑coil, but limited changes to β‑sheet content, in PG12. Thioflavin T fluorescence tests indicated that fluorescent value was increased in PG5 subjected to redox. In addition, proteinase K (PK) digestions indicated that PK resistance was stronger in PG12 and PG0 compared with in PG5; redox enhanced the PK resistance of all three PrP constructs, particularly PG0 and PG12. These data indicated that formation of a disulfide bond induces marked alterations in the secondary structure and biochemical characteristics of PrP. In addition, the octarepeat region within the PrP peptide markedly influences the effects of redox on the biochemical phenotypes of PrP, thus highlighting the importance of the number of octarepeats in the biological functions of PrP.

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Section: Discussionsupporting

confidence: 94%

Redox induces diverse effects on recombinant human wild-type PrP and mutated PrP with inserted or deleted octarepeats

et al. 2018

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“…Previous studies of the trace element status in brains of patients with sporadic CJD showed a decrease of Cu 2þ and an increase in Mn 2þ of approximately 10 folds [143][144][145]. Although the binding affinity of Mn 2þ to PrP C is relatively lower compared with Cu 2þ , it does result in an increase of b-sheet content in prion protein conformation [146][147][148].…”

Section: Metalsmentioning

confidence: 95%

Conformational conversion of prion protein in prion diseases

Zhou¹,

Xiao²

2013

ABBS

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Prion diseases are a group of infectious fatal neurodegenerative diseases. The conformational conversion of a cellular prion protein (PrP(C)) into an abnormal misfolded isoform (PrP(Sc)) is the key event in prion diseases pathology. Under normal conditions, the high-energy barrier separates PrP(C) from PrP(Sc) isoform. However, pathogenic mutations, modifications as well as some cofactors, such as glycosaminoglycans, nucleic acids, and lipids, could modulate the conformational conversion process. Understanding the mechanism of conformational conversion of prion protein is essential for the biomedical research and the treatment of prion diseases. Particularly, the characterization of cofactors interacting with prion protein might provide new diagnostic and therapeutic strategies.

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“…This effect was inhibited by the addition of Cu 2+ [ 95 ]. The observation that Mn-treatment of normal hamster brain homogenate was able to enhance the efficiency of PrP C conversion in the presence of a catalytic amount of PrP Sc seed helps support the notion that Mn 2+ may facilitate the de novo generation of PrP Sc in vivo [ 99 , 100 ].…”

Section: Prion Protein Aggregation In Prion Diseasementioning

confidence: 81%

Antioxidant and Metal Chelation-Based Therapies in the Treatment of Prion Disease

2014

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Many neurodegenerative disorders involve the accumulation of multimeric assemblies and amyloid derived from misfolded conformers of constitutively expressed proteins. In addition, the brains of patients and experimental animals afflicted with prion disease display evidence of heightened oxidative stress and damage, as well as disturbances to transition metal homeostasis. Utilising a variety of disease model paradigms, many laboratories have demonstrated that copper can act as a cofactor in the antioxidant activity displayed by the prion protein while manganese has been implicated in the generation and stabilisation of disease-associated conformers. This and other evidence has led several groups to test dietary and chelation therapy-based regimens to manipulate brain metal concentrations in attempts to influence the progression of prion disease in experimental mice. Results have been inconsistent. This review examines published data on transition metal dyshomeostasis, free radical generation and subsequent oxidative damage in the pathogenesis of prion disease. It also comments on the efficacy of trialed therapeutics chosen to combat such deleterious changes.

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Manganese-induced changes of the biochemical characteristics of the recombinant wild-type and mutant PrPs

Cited by 12 publications

References 29 publications

Redox induces diverse effects on recombinant human wild-type PrP and mutated PrP with inserted or deleted octarepeats

Redox induces diverse effects on recombinant human wild-type PrP and mutated PrP with inserted or deleted octarepeats

Conformational conversion of prion protein in prion diseases

Antioxidant and Metal Chelation-Based Therapies in the Treatment of Prion Disease

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