A high-content neuron imaging assay demonstrates inhibition of prion disease-associated neurotoxicity by an anti-prion protein antibody
Abstract There is an urgent need to develop disease-modifying therapies to treat neurodegenerative diseases which pose increasing challenges to global healthcare systems. Prion diseases, although rare, provide a paradigm to study neurodegenerative dementias as similar disease mechanisms involving pr...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-06-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-13455-z |
| _version_ | 1818207666561875968 |
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| author | Madeleine Reilly Iryna Benilova Azadeh Khalili-Shirazi Christian Schmidt Parvin Ahmed Daniel Yip Parmjit S. Jat John Collinge |
| author_facet | Madeleine Reilly Iryna Benilova Azadeh Khalili-Shirazi Christian Schmidt Parvin Ahmed Daniel Yip Parmjit S. Jat John Collinge |
| author_sort | Madeleine Reilly |
| collection | DOAJ |
| description | Abstract There is an urgent need to develop disease-modifying therapies to treat neurodegenerative diseases which pose increasing challenges to global healthcare systems. Prion diseases, although rare, provide a paradigm to study neurodegenerative dementias as similar disease mechanisms involving propagation and spread of multichain assemblies of misfolded protein (“prion-like” mechanisms) are increasingly recognised in the commoner conditions such as Alzheimer’s disease. However, studies of prion disease pathogenesis in mouse models showed that prion propagation and neurotoxicity can be mechanistically uncoupled and in vitro assays confirmed that highly purified prions are indeed not directly neurotoxic. To aid development of prion disease therapeutics we have therefore developed a cell-based assay for the specific neurotoxicity seen in prion diseases rather than to simply assess inhibition of prion propagation. We applied this assay to examine an anti-prion protein mouse monoclonal antibody (ICSM18) known to potently cure prion-infected cells and to delay onset of prion disease in prion-infected mice. We demonstrate that whilst ICSM18 itself lacks inherent neurotoxicity in this assay, it potently blocks prion disease-associated neurotoxicity. |
| first_indexed | 2024-12-12T04:32:33Z |
| format | Article |
| id | doaj.art-6c3d427e537748449f547bcad8e6d4f9 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-12T04:32:33Z |
| publishDate | 2022-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-6c3d427e537748449f547bcad8e6d4f92022-12-22T00:38:02ZengNature PortfolioScientific Reports2045-23222022-06-0112111210.1038/s41598-022-13455-zA high-content neuron imaging assay demonstrates inhibition of prion disease-associated neurotoxicity by an anti-prion protein antibodyMadeleine Reilly0Iryna Benilova1Azadeh Khalili-Shirazi2Christian Schmidt3Parvin Ahmed4Daniel Yip5Parmjit S. Jat6John Collinge7MRC Prion Unit at UCL, UCL Institute of Prion Diseases, University College LondonMRC Prion Unit at UCL, UCL Institute of Prion Diseases, University College LondonMRC Prion Unit at UCL, UCL Institute of Prion Diseases, University College LondonMRC Prion Unit at UCL, UCL Institute of Prion Diseases, University College LondonMRC Prion Unit at UCL, UCL Institute of Prion Diseases, University College LondonMRC Prion Unit at UCL, UCL Institute of Prion Diseases, University College LondonMRC Prion Unit at UCL, UCL Institute of Prion Diseases, University College LondonMRC Prion Unit at UCL, UCL Institute of Prion Diseases, University College LondonAbstract There is an urgent need to develop disease-modifying therapies to treat neurodegenerative diseases which pose increasing challenges to global healthcare systems. Prion diseases, although rare, provide a paradigm to study neurodegenerative dementias as similar disease mechanisms involving propagation and spread of multichain assemblies of misfolded protein (“prion-like” mechanisms) are increasingly recognised in the commoner conditions such as Alzheimer’s disease. However, studies of prion disease pathogenesis in mouse models showed that prion propagation and neurotoxicity can be mechanistically uncoupled and in vitro assays confirmed that highly purified prions are indeed not directly neurotoxic. To aid development of prion disease therapeutics we have therefore developed a cell-based assay for the specific neurotoxicity seen in prion diseases rather than to simply assess inhibition of prion propagation. We applied this assay to examine an anti-prion protein mouse monoclonal antibody (ICSM18) known to potently cure prion-infected cells and to delay onset of prion disease in prion-infected mice. We demonstrate that whilst ICSM18 itself lacks inherent neurotoxicity in this assay, it potently blocks prion disease-associated neurotoxicity.https://doi.org/10.1038/s41598-022-13455-z |
| spellingShingle | Madeleine Reilly Iryna Benilova Azadeh Khalili-Shirazi Christian Schmidt Parvin Ahmed Daniel Yip Parmjit S. Jat John Collinge A high-content neuron imaging assay demonstrates inhibition of prion disease-associated neurotoxicity by an anti-prion protein antibody Scientific Reports |
| title | A high-content neuron imaging assay demonstrates inhibition of prion disease-associated neurotoxicity by an anti-prion protein antibody |
| title_full | A high-content neuron imaging assay demonstrates inhibition of prion disease-associated neurotoxicity by an anti-prion protein antibody |
| title_fullStr | A high-content neuron imaging assay demonstrates inhibition of prion disease-associated neurotoxicity by an anti-prion protein antibody |
| title_full_unstemmed | A high-content neuron imaging assay demonstrates inhibition of prion disease-associated neurotoxicity by an anti-prion protein antibody |
| title_short | A high-content neuron imaging assay demonstrates inhibition of prion disease-associated neurotoxicity by an anti-prion protein antibody |
| title_sort | high content neuron imaging assay demonstrates inhibition of prion disease associated neurotoxicity by an anti prion protein antibody |
| url | https://doi.org/10.1038/s41598-022-13455-z |
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