Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity
<p>Synucleinopathies including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are characterized by pathological accumulation of α-synuclein (α-syn). Amongst the various approaches attempting to tackle the pathological features of synucleinopathies,...
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2020
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| _version_ | 1864513512968028160 |
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| author | Vijay Gupta (209146) |
| author2 | Safa Salim (9186786) Issam Hmila (9239059) Nishant N. Vaikath (2901785) Indulekha P. Sudhakaran (9611154) Simona S. Ghanem (12267227) Nour K. Majbour (8809316) Sara A. Abdulla (13902015) Mohamed M. Emara (9913215) Houari B. Abdesselem (14152827) Tamas Lukacsovich (23182) Daniel Erskine (3471959) Omar M. A. El-Agnaf (8809331) |
| author2_role | author author author author author author author author author author author author |
| author_facet | Vijay Gupta (209146) Safa Salim (9186786) Issam Hmila (9239059) Nishant N. Vaikath (2901785) Indulekha P. Sudhakaran (9611154) Simona S. Ghanem (12267227) Nour K. Majbour (8809316) Sara A. Abdulla (13902015) Mohamed M. Emara (9913215) Houari B. Abdesselem (14152827) Tamas Lukacsovich (23182) Daniel Erskine (3471959) Omar M. A. El-Agnaf (8809331) |
| author_role | author |
| dc.creator.none.fl_str_mv | Vijay Gupta (209146) Safa Salim (9186786) Issam Hmila (9239059) Nishant N. Vaikath (2901785) Indulekha P. Sudhakaran (9611154) Simona S. Ghanem (12267227) Nour K. Majbour (8809316) Sara A. Abdulla (13902015) Mohamed M. Emara (9913215) Houari B. Abdesselem (14152827) Tamas Lukacsovich (23182) Daniel Erskine (3471959) Omar M. A. El-Agnaf (8809331) |
| dc.date.none.fl_str_mv | 2020-05-18T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1038/s41598-020-65035-8 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Fibrillar_form_of_-synuclein-specific_scFv_antibody_inhibits_-synuclein_seeds_induced_aggregation_and_toxicity/21598173 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Biochemistry and cell biology Biomedical and clinical sciences Neurosciences Parkinson's disease Dementia with Lewy bodies Multiple system atrophy Neurodegeneration Immunotherapy Antibody engineering Protein purification |
| dc.title.none.fl_str_mv | Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p>Synucleinopathies including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are characterized by pathological accumulation of α-synuclein (α-syn). Amongst the various approaches attempting to tackle the pathological features of synucleinopathies, antibody-based immunotherapy holds much promise. However, the large size of antibodies and corresponding difficulty in crossing the blood-brain barrier has limited development in this area. To overcome this issue, we engineered single-chain variable fragments (scFvs) against fibrillar α-syn, a putative disease-relevant form of α-syn. The purified scFvs showed specific activity towards α-syn fibrils and oligomers in comparison to monomers and recognized intracellular inclusions in human post-mortem brain tissue of Lewy body disease cases, but not aged controls. In vitro studies indicated scFvs inhibit the seeding of α-syn aggregation in a time-dependent manner, decreased α-syn seed-induced toxicity in a cell model of PD, and reduced the production of insoluble α-syn phosphorylated at Ser-129 (pS129-α-syn). These results suggest that our α-syn fibril-specific scFvs recognize α-syn pathology and can inhibit the aggregation of α-syn in vitro and prevent seeding-dependent toxicity. Therefore, the scFvs described here have considerable potential to be utilized towards immunotherapy in synucleinopathies and may also have applications in ante-mortem imaging modalities.</p><h2>Other Information</h2> <p> Published in: Scientific Reports<br> License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="http://dx.doi.org/10.1038/s41598-020-65035-8" target="_blank">http://dx.doi.org/10.1038/s41598-020-65035-8</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_c6908f2e1672bedecbd970e0e303cab5 |
| identifier_str_mv | 10.1038/s41598-020-65035-8 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/21598173 |
| publishDate | 2020 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicityVijay Gupta (209146)Safa Salim (9186786)Issam Hmila (9239059)Nishant N. Vaikath (2901785)Indulekha P. Sudhakaran (9611154)Simona S. Ghanem (12267227)Nour K. Majbour (8809316)Sara A. Abdulla (13902015)Mohamed M. Emara (9913215)Houari B. Abdesselem (14152827)Tamas Lukacsovich (23182)Daniel Erskine (3471959)Omar M. A. El-Agnaf (8809331)Biological sciencesBiochemistry and cell biologyBiomedical and clinical sciencesNeurosciencesParkinson's diseaseDementia with Lewy bodiesMultiple system atrophyNeurodegenerationImmunotherapyAntibody engineeringProtein purification<p>Synucleinopathies including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are characterized by pathological accumulation of α-synuclein (α-syn). Amongst the various approaches attempting to tackle the pathological features of synucleinopathies, antibody-based immunotherapy holds much promise. However, the large size of antibodies and corresponding difficulty in crossing the blood-brain barrier has limited development in this area. To overcome this issue, we engineered single-chain variable fragments (scFvs) against fibrillar α-syn, a putative disease-relevant form of α-syn. The purified scFvs showed specific activity towards α-syn fibrils and oligomers in comparison to monomers and recognized intracellular inclusions in human post-mortem brain tissue of Lewy body disease cases, but not aged controls. In vitro studies indicated scFvs inhibit the seeding of α-syn aggregation in a time-dependent manner, decreased α-syn seed-induced toxicity in a cell model of PD, and reduced the production of insoluble α-syn phosphorylated at Ser-129 (pS129-α-syn). These results suggest that our α-syn fibril-specific scFvs recognize α-syn pathology and can inhibit the aggregation of α-syn in vitro and prevent seeding-dependent toxicity. Therefore, the scFvs described here have considerable potential to be utilized towards immunotherapy in synucleinopathies and may also have applications in ante-mortem imaging modalities.</p><h2>Other Information</h2> <p> Published in: Scientific Reports<br> License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="http://dx.doi.org/10.1038/s41598-020-65035-8" target="_blank">http://dx.doi.org/10.1038/s41598-020-65035-8</a></p>2020-05-18T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1038/s41598-020-65035-8https://figshare.com/articles/journal_contribution/Fibrillar_form_of_-synuclein-specific_scFv_antibody_inhibits_-synuclein_seeds_induced_aggregation_and_toxicity/21598173CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/215981732020-05-18T03:00:00Z |
| spellingShingle | Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity Vijay Gupta (209146) Biological sciences Biochemistry and cell biology Biomedical and clinical sciences Neurosciences Parkinson's disease Dementia with Lewy bodies Multiple system atrophy Neurodegeneration Immunotherapy Antibody engineering Protein purification |
| status_str | publishedVersion |
| title | Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity |
| title_full | Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity |
| title_fullStr | Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity |
| title_full_unstemmed | Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity |
| title_short | Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity |
| title_sort | Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity |
| topic | Biological sciences Biochemistry and cell biology Biomedical and clinical sciences Neurosciences Parkinson's disease Dementia with Lewy bodies Multiple system atrophy Neurodegeneration Immunotherapy Antibody engineering Protein purification |