Globular and pre-fibrillar prion aggregates are toxic to neuronal cells and perturb their electrophysiology.
Prion diseases are characterised at autopsy by neuronal loss and accumulation of amorphous protein aggregates and/or amyloid fibrils in the brains of humans and animals. These protein deposits result from the conversion of the cellular, mainly alpha-helical prion protein (PrP(C)) to the beta-sheet-r...
| Main Authors: | , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2008
|
| _version_ | 1826261678081179648 |
|---|---|
| author | Sanghera, N Wall, M Vénien-Bryan, C Pinheiro, T |
| author_facet | Sanghera, N Wall, M Vénien-Bryan, C Pinheiro, T |
| author_sort | Sanghera, N |
| collection | OXFORD |
| description | Prion diseases are characterised at autopsy by neuronal loss and accumulation of amorphous protein aggregates and/or amyloid fibrils in the brains of humans and animals. These protein deposits result from the conversion of the cellular, mainly alpha-helical prion protein (PrP(C)) to the beta-sheet-rich isoform (PrP(Sc)). Although the pathogenic mechanism of prion diseases is not fully understood, it appears that protein aggregation is itself neurotoxic and not the product of cell death. The precise nature of the neurotoxic species and mechanism of cell death are yet to be determined, although recent studies with other amyloidogenic proteins suggest that ordered pre-fibrillar or oligomeric forms may be responsible for cellular dysfunction. In this study we have refolded recombinant prion protein (rPrP) to two distinct forms rich in beta-sheet structure with an intact disulphide bond. Here we report on the structural properties of globular aggregates and pre-fibrils of rPrP and show that both states are toxic to neuronal cells in culture. We show that exogenous rPrP aggregates are internalised by neuronal cells and found in the cytoplasm. We also measured the changes in electrophysiological properties of cultured neuronal cells on exposure to exogenous prion aggregates and discuss the implications of these findings. |
| first_indexed | 2024-03-06T19:25:07Z |
| format | Journal article |
| id | oxford-uuid:1b6f88b2-c312-4f73-9fda-aceba7854df1 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T19:25:07Z |
| publishDate | 2008 |
| record_format | dspace |
| spelling | oxford-uuid:1b6f88b2-c312-4f73-9fda-aceba7854df12022-03-26T11:00:20ZGlobular and pre-fibrillar prion aggregates are toxic to neuronal cells and perturb their electrophysiology.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:1b6f88b2-c312-4f73-9fda-aceba7854df1EnglishSymplectic Elements at Oxford2008Sanghera, NWall, MVénien-Bryan, CPinheiro, TPrion diseases are characterised at autopsy by neuronal loss and accumulation of amorphous protein aggregates and/or amyloid fibrils in the brains of humans and animals. These protein deposits result from the conversion of the cellular, mainly alpha-helical prion protein (PrP(C)) to the beta-sheet-rich isoform (PrP(Sc)). Although the pathogenic mechanism of prion diseases is not fully understood, it appears that protein aggregation is itself neurotoxic and not the product of cell death. The precise nature of the neurotoxic species and mechanism of cell death are yet to be determined, although recent studies with other amyloidogenic proteins suggest that ordered pre-fibrillar or oligomeric forms may be responsible for cellular dysfunction. In this study we have refolded recombinant prion protein (rPrP) to two distinct forms rich in beta-sheet structure with an intact disulphide bond. Here we report on the structural properties of globular aggregates and pre-fibrils of rPrP and show that both states are toxic to neuronal cells in culture. We show that exogenous rPrP aggregates are internalised by neuronal cells and found in the cytoplasm. We also measured the changes in electrophysiological properties of cultured neuronal cells on exposure to exogenous prion aggregates and discuss the implications of these findings. |
| spellingShingle | Sanghera, N Wall, M Vénien-Bryan, C Pinheiro, T Globular and pre-fibrillar prion aggregates are toxic to neuronal cells and perturb their electrophysiology. |
| title | Globular and pre-fibrillar prion aggregates are toxic to neuronal cells and perturb their electrophysiology. |
| title_full | Globular and pre-fibrillar prion aggregates are toxic to neuronal cells and perturb their electrophysiology. |
| title_fullStr | Globular and pre-fibrillar prion aggregates are toxic to neuronal cells and perturb their electrophysiology. |
| title_full_unstemmed | Globular and pre-fibrillar prion aggregates are toxic to neuronal cells and perturb their electrophysiology. |
| title_short | Globular and pre-fibrillar prion aggregates are toxic to neuronal cells and perturb their electrophysiology. |
| title_sort | globular and pre fibrillar prion aggregates are toxic to neuronal cells and perturb their electrophysiology |
| work_keys_str_mv | AT sangheran globularandprefibrillarprionaggregatesaretoxictoneuronalcellsandperturbtheirelectrophysiology AT wallm globularandprefibrillarprionaggregatesaretoxictoneuronalcellsandperturbtheirelectrophysiology AT venienbryanc globularandprefibrillarprionaggregatesaretoxictoneuronalcellsandperturbtheirelectrophysiology AT pinheirot globularandprefibrillarprionaggregatesaretoxictoneuronalcellsandperturbtheirelectrophysiology |