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Manganese-induced changes of the biochemical characteristics of the recombinant wild-type and mutant PrPs
Xiao-Li Li1, Chen-Fang Dong, Gui-Rong Wang
1State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China.
Abstract:
Manganese may play some roles in the pathogenesis of prion diseases. In this study, recombinant human wild-type (WT) PrP and PrP mutants with deleted or inserted octarepeats were exposed to manganese, and their biochemical and biophysical characteristics were evaluated by proteinase K (PK) digestion, sedimentation experiments, transmission electron microscopy and circular dichroism. It demonstrated that incubation of manganese remarkably increased PK-resistances, protein aggregations and beta-sheet contents of the PrPs. Moreover, the PrP mutants of inserted or deleted octarepeats were much vulnerable to the influence of manganese, which showed obviously more aggregation and higher beta-sheet content than that of WT-PrP. It highlights that the effect of manganese on the PrP seems to lie on the incorrectness of the octarepeats numbers. The association of the octarepeats number of PrP with manganese may further provide insight into the unresolved biological function of PrP in the neurons.
Insights
Manganese exposure increases prion protein (PrP) aggregation and resistance to degradation. Variations in PrP octarepeats amplify these manganese-induced effects, suggesting a role in prion disease pathogenesis.
Area of Science:
- Neuroscience
- Biochemistry
- Prion Disease Research
Background:
- Prion diseases are linked to misfolded prion proteins (PrP).
- Manganese is a metal ion present in the brain, and its role in prion pathogenesis is under investigation.
- The octarepeat region of PrP is known to bind metal ions, but its specific role in manganese-induced changes is unclear.
Purpose of the Study:
- To investigate the impact of manganese on the biochemical and biophysical properties of wild-type (WT) human prion protein (PrP) and its mutants.
- To determine if alterations in the octarepeat number affect manganese's influence on PrP structure and aggregation.
Main Methods:
- Recombinant WT PrP and PrP mutants with altered octarepeats were incubated with manganese.
- Proteinase K (PK) digestion was used to assess proteinase resistance.
- Sedimentation experiments, transmission electron microscopy (TEM), and circular dichroism (CD) were employed to evaluate protein aggregation and secondary structure changes.
Main Results:
- Manganese incubation significantly increased PrP's resistance to PK digestion.
- Manganese exposure led to enhanced protein aggregation and increased beta-sheet content in PrP.
- PrP mutants with deleted or inserted octarepeats exhibited greater aggregation and higher beta-sheet content upon manganese exposure compared to WT PrP.
Conclusions:
- The number of octarepeats in PrP is critical in modulating the effects of manganese.
- Manganese-induced changes in PrP, particularly aggregation and altered structure, are influenced by octarepeat variations.
- These findings suggest a potential link between manganese, PrP octarepeat numbers, and the pathogenesis of prion diseases, offering insights into PrP's biological function.
