CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease
Parkinson’s disease (PD) affects millions of patients worldwide and is characterized by alpha-synuclein aggregation in dopamine neurons. Molecular tweezers have shown high potential as anti-aggregation agents targeting positively charged residues of proteins undergoing amyloidogenic processes. Here...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Springer Nature
2020
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| _version_ | 1797063194434338816 |
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| author | Bengoa-Vergniory, N Faggiani, E Ramos-Gonzalez, P Kirkiz, E Connor-Robson, N Brown, L Siddique, I Li, Z Vingill, S Cioroch, M Cavaliere, F Threlfell, S Roberts, B Schrader, T Klärner, F-G Cragg, S Gal Bitan Dehay, B Matute, C Bezard, E Wade-Martins, R |
| author_facet | Bengoa-Vergniory, N Faggiani, E Ramos-Gonzalez, P Kirkiz, E Connor-Robson, N Brown, L Siddique, I Li, Z Vingill, S Cioroch, M Cavaliere, F Threlfell, S Roberts, B Schrader, T Klärner, F-G Cragg, S Gal Bitan Dehay, B Matute, C Bezard, E Wade-Martins, R |
| author_sort | Bengoa-Vergniory, N |
| collection | OXFORD |
| description | Parkinson’s disease (PD) affects millions of patients worldwide and is characterized by alpha-synuclein aggregation in dopamine neurons. Molecular tweezers have shown high potential as anti-aggregation agents targeting positively charged residues of proteins undergoing amyloidogenic processes. Here we report that the molecular tweezer CLR01 decreased aggregation and toxicity in induced pluripotent stem cell-derived dopaminergic cultures treated with PD brain protein extracts. In microfluidic devices CLR01 reduced alpha-synuclein aggregation in cell somas when axonal terminals were exposed to alpha-synuclein oligomers. We then tested CLR01 in vivo in a humanized alpha-synuclein overexpressing mouse model; mice treated at 12 months of age when motor defects are mild exhibited an improvement in motor defects and a decreased oligomeric alpha-synuclein burden. Finally, CLR01 reduced alpha-synuclein-associated pathology in mice injected with alpha-synuclein aggregates into the striatum or substantia nigra. Taken together, these results highlight CLR01 as a disease-modifying therapy for PD and support further clinical investigation. |
| first_indexed | 2024-03-06T20:56:19Z |
| format | Journal article |
| id | oxford-uuid:396382e2-85cf-4517-a1a8-40d1b94c0590 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:56:19Z |
| publishDate | 2020 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:396382e2-85cf-4517-a1a8-40d1b94c05902022-03-26T13:55:16ZCLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s diseaseJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:396382e2-85cf-4517-a1a8-40d1b94c0590EnglishSymplectic ElementsSpringer Nature2020Bengoa-Vergniory, NFaggiani, ERamos-Gonzalez, PKirkiz, EConnor-Robson, NBrown, LSiddique, ILi, ZVingill, SCioroch, MCavaliere, FThrelfell, SRoberts, BSchrader, TKlärner, F-GCragg, SGal BitanDehay, BMatute, CBezard, EWade-Martins, RParkinson’s disease (PD) affects millions of patients worldwide and is characterized by alpha-synuclein aggregation in dopamine neurons. Molecular tweezers have shown high potential as anti-aggregation agents targeting positively charged residues of proteins undergoing amyloidogenic processes. Here we report that the molecular tweezer CLR01 decreased aggregation and toxicity in induced pluripotent stem cell-derived dopaminergic cultures treated with PD brain protein extracts. In microfluidic devices CLR01 reduced alpha-synuclein aggregation in cell somas when axonal terminals were exposed to alpha-synuclein oligomers. We then tested CLR01 in vivo in a humanized alpha-synuclein overexpressing mouse model; mice treated at 12 months of age when motor defects are mild exhibited an improvement in motor defects and a decreased oligomeric alpha-synuclein burden. Finally, CLR01 reduced alpha-synuclein-associated pathology in mice injected with alpha-synuclein aggregates into the striatum or substantia nigra. Taken together, these results highlight CLR01 as a disease-modifying therapy for PD and support further clinical investigation. |
| spellingShingle | Bengoa-Vergniory, N Faggiani, E Ramos-Gonzalez, P Kirkiz, E Connor-Robson, N Brown, L Siddique, I Li, Z Vingill, S Cioroch, M Cavaliere, F Threlfell, S Roberts, B Schrader, T Klärner, F-G Cragg, S Gal Bitan Dehay, B Matute, C Bezard, E Wade-Martins, R CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease |
| title | CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease |
| title_full | CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease |
| title_fullStr | CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease |
| title_full_unstemmed | CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease |
| title_short | CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease |
| title_sort | clr01 protects dopaminergic neurons in vitro and in mouse models of parkinson s disease |
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