Small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegans
<h3>Background</h3><p dir="ltr">Parkinson’s disease is a disabling neurodegenerative movement disorder characterized by dopaminergic neuron loss induced by α-synuclein oligomers. There is an urgent need for disease-modifying therapies for Parkinson’s disease, but drug dis...
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2021
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| author | Kevin S. Chen (9201767) |
| author2 | Krystal Menezes (11692035) Jarlath B. Rodgers (2873462) Darren M. O’Hara (9201761) Nhat Tran (10733310) Kazuko Fujisawa (11692038) Seiya Ishikura (11692041) Shahin Khodaei (11692044) Hien Chau (355945) Anna Cranston (11692047) Minesh Kapadia (582056) Grishma Pawar (10666899) Susan Ping (11692050) Aldis Krizus (4253764) Alix Lacoste (11692053) Scott Spangler (4499941) Naomi P. Visanji (11692056) Connie Marras (3540161) Nour K. Majbour (8809316) Omar M. A. El-Agnaf (8809331) Andres M. Lozano (8627790) Joseph Culotti (11692059) Satoshi Suo (446967) William S. Ryu (8630016) Suneil K. Kalia (9201773) Lorraine V. Kalia (9201770) |
| author2_role | author author author author author author author author author author author author author author author author author author author author author author author author author |
| author_facet | Kevin S. Chen (9201767) Krystal Menezes (11692035) Jarlath B. Rodgers (2873462) Darren M. O’Hara (9201761) Nhat Tran (10733310) Kazuko Fujisawa (11692038) Seiya Ishikura (11692041) Shahin Khodaei (11692044) Hien Chau (355945) Anna Cranston (11692047) Minesh Kapadia (582056) Grishma Pawar (10666899) Susan Ping (11692050) Aldis Krizus (4253764) Alix Lacoste (11692053) Scott Spangler (4499941) Naomi P. Visanji (11692056) Connie Marras (3540161) Nour K. Majbour (8809316) Omar M. A. El-Agnaf (8809331) Andres M. Lozano (8627790) Joseph Culotti (11692059) Satoshi Suo (446967) William S. Ryu (8630016) Suneil K. Kalia (9201773) Lorraine V. Kalia (9201770) |
| author_role | author |
| dc.creator.none.fl_str_mv | Kevin S. Chen (9201767) Krystal Menezes (11692035) Jarlath B. Rodgers (2873462) Darren M. O’Hara (9201761) Nhat Tran (10733310) Kazuko Fujisawa (11692038) Seiya Ishikura (11692041) Shahin Khodaei (11692044) Hien Chau (355945) Anna Cranston (11692047) Minesh Kapadia (582056) Grishma Pawar (10666899) Susan Ping (11692050) Aldis Krizus (4253764) Alix Lacoste (11692053) Scott Spangler (4499941) Naomi P. Visanji (11692056) Connie Marras (3540161) Nour K. Majbour (8809316) Omar M. A. El-Agnaf (8809331) Andres M. Lozano (8627790) Joseph Culotti (11692059) Satoshi Suo (446967) William S. Ryu (8630016) Suneil K. Kalia (9201773) Lorraine V. Kalia (9201770) |
| dc.date.none.fl_str_mv | 2021-11-12T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1186/s13024-021-00497-6 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Small_molecule_inhibitors_of_-synuclein_oligomers_identified_by_targeting_early_dopamine-mediated_motor_impairment_in_C_elegans/25771977 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Neurosciences Pharmacology and pharmaceutical sciences Information and computing sciences Machine learning Alpha-synuclein Animal model Artificial intelligence Drug discovery Machine learning Natural language processing Neurodegeneration Oligomers Parkinson’s disease |
| dc.title.none.fl_str_mv | Small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegans |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <h3>Background</h3><p dir="ltr">Parkinson’s disease is a disabling neurodegenerative movement disorder characterized by dopaminergic neuron loss induced by α-synuclein oligomers. There is an urgent need for disease-modifying therapies for Parkinson’s disease, but drug discovery is challenged by lack of in vivo models that recapitulate early stages of neurodegeneration. Invertebrate organisms, such as the nematode worm Caenorhabditis elegans, provide in vivo models of human disease processes that can be instrumental for initial pharmacological studies.</p><h3>Methods</h3><p dir="ltr">To identify early motor impairment of animals expressing α-synuclein in dopaminergic neurons, we first used a custom-built tracking microscope that captures locomotion of single C. elegans with high spatial and temporal resolution. Next, we devised a method for semi-automated and blinded quantification of motor impairment for a population of simultaneously recorded animals with multi-worm tracking and custom image processing. We then used genetic and pharmacological methods to define the features of early motor dysfunction of α-synuclein-expressing C. elegans. Finally, we applied the C. elegans model to a drug repurposing screen by combining it with an artificial intelligence platform and cell culture system to identify small molecules that inhibit α-synuclein oligomers. Screen hits were validated using in vitro and in vivo mammalian models.</p><h3>Results</h3><p dir="ltr">We found a previously undescribed motor phenotype in transgenic α-synuclein C. elegans that correlates with mutant or wild-type α-synuclein protein levels and results from dopaminergic neuron dysfunction, but precedes neuronal loss. Together with artificial intelligence-driven in silico and in vitro screening, this C. elegans model identified five compounds that reduced motor dysfunction induced by α-synuclein. Three of these compounds also decreased α-synuclein oligomers in mammalian neurons, including rifabutin which has not been previously investigated for Parkinson’s disease. We found that treatment with rifabutin reduced nigrostriatal dopaminergic neurodegeneration due to α-synuclein in a rat model.</p><h3>Conclusions</h3><p dir="ltr">We identified a C. elegans locomotor abnormality due to dopaminergic neuron dysfunction that models early α-synuclein-mediated neurodegeneration. Our innovative approach applying this in vivo model to a multi-step drug repurposing screen, with artificial intelligence-driven in silico and in vitro methods, resulted in the discovery of at least one drug that may be repurposed as a disease-modifying therapy for Parkinson’s disease.</p><h2>Other Information</h2><p dir="ltr">Published in: Molecular Neurodegeneration<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="https://dx.doi.org/10.1186/s13024-021-00497-6" target="_blank">https://dx.doi.org/10.1186/s13024-021-00497-6</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_5aae25e67d4d8cabbc6d80936bda9efb |
| identifier_str_mv | 10.1186/s13024-021-00497-6 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25771977 |
| publishDate | 2021 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegansKevin S. Chen (9201767)Krystal Menezes (11692035)Jarlath B. Rodgers (2873462)Darren M. O’Hara (9201761)Nhat Tran (10733310)Kazuko Fujisawa (11692038)Seiya Ishikura (11692041)Shahin Khodaei (11692044)Hien Chau (355945)Anna Cranston (11692047)Minesh Kapadia (582056)Grishma Pawar (10666899)Susan Ping (11692050)Aldis Krizus (4253764)Alix Lacoste (11692053)Scott Spangler (4499941)Naomi P. Visanji (11692056)Connie Marras (3540161)Nour K. Majbour (8809316)Omar M. A. El-Agnaf (8809331)Andres M. Lozano (8627790)Joseph Culotti (11692059)Satoshi Suo (446967)William S. Ryu (8630016)Suneil K. Kalia (9201773)Lorraine V. Kalia (9201770)Biomedical and clinical sciencesNeurosciencesPharmacology and pharmaceutical sciencesInformation and computing sciencesMachine learningAlpha-synucleinAnimal modelArtificial intelligenceDrug discoveryMachine learningNatural language processingNeurodegenerationOligomersParkinson’s disease<h3>Background</h3><p dir="ltr">Parkinson’s disease is a disabling neurodegenerative movement disorder characterized by dopaminergic neuron loss induced by α-synuclein oligomers. There is an urgent need for disease-modifying therapies for Parkinson’s disease, but drug discovery is challenged by lack of in vivo models that recapitulate early stages of neurodegeneration. Invertebrate organisms, such as the nematode worm Caenorhabditis elegans, provide in vivo models of human disease processes that can be instrumental for initial pharmacological studies.</p><h3>Methods</h3><p dir="ltr">To identify early motor impairment of animals expressing α-synuclein in dopaminergic neurons, we first used a custom-built tracking microscope that captures locomotion of single C. elegans with high spatial and temporal resolution. Next, we devised a method for semi-automated and blinded quantification of motor impairment for a population of simultaneously recorded animals with multi-worm tracking and custom image processing. We then used genetic and pharmacological methods to define the features of early motor dysfunction of α-synuclein-expressing C. elegans. Finally, we applied the C. elegans model to a drug repurposing screen by combining it with an artificial intelligence platform and cell culture system to identify small molecules that inhibit α-synuclein oligomers. Screen hits were validated using in vitro and in vivo mammalian models.</p><h3>Results</h3><p dir="ltr">We found a previously undescribed motor phenotype in transgenic α-synuclein C. elegans that correlates with mutant or wild-type α-synuclein protein levels and results from dopaminergic neuron dysfunction, but precedes neuronal loss. Together with artificial intelligence-driven in silico and in vitro screening, this C. elegans model identified five compounds that reduced motor dysfunction induced by α-synuclein. Three of these compounds also decreased α-synuclein oligomers in mammalian neurons, including rifabutin which has not been previously investigated for Parkinson’s disease. We found that treatment with rifabutin reduced nigrostriatal dopaminergic neurodegeneration due to α-synuclein in a rat model.</p><h3>Conclusions</h3><p dir="ltr">We identified a C. elegans locomotor abnormality due to dopaminergic neuron dysfunction that models early α-synuclein-mediated neurodegeneration. Our innovative approach applying this in vivo model to a multi-step drug repurposing screen, with artificial intelligence-driven in silico and in vitro methods, resulted in the discovery of at least one drug that may be repurposed as a disease-modifying therapy for Parkinson’s disease.</p><h2>Other Information</h2><p dir="ltr">Published in: Molecular Neurodegeneration<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="https://dx.doi.org/10.1186/s13024-021-00497-6" target="_blank">https://dx.doi.org/10.1186/s13024-021-00497-6</a></p>2021-11-12T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1186/s13024-021-00497-6https://figshare.com/articles/journal_contribution/Small_molecule_inhibitors_of_-synuclein_oligomers_identified_by_targeting_early_dopamine-mediated_motor_impairment_in_C_elegans/25771977CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/257719772021-11-12T03:00:00Z |
| spellingShingle | Small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegans Kevin S. Chen (9201767) Biomedical and clinical sciences Neurosciences Pharmacology and pharmaceutical sciences Information and computing sciences Machine learning Alpha-synuclein Animal model Artificial intelligence Drug discovery Machine learning Natural language processing Neurodegeneration Oligomers Parkinson’s disease |
| status_str | publishedVersion |
| title | Small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegans |
| title_full | Small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegans |
| title_fullStr | Small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegans |
| title_full_unstemmed | Small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegans |
| title_short | Small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegans |
| title_sort | Small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegans |
| topic | Biomedical and clinical sciences Neurosciences Pharmacology and pharmaceutical sciences Information and computing sciences Machine learning Alpha-synuclein Animal model Artificial intelligence Drug discovery Machine learning Natural language processing Neurodegeneration Oligomers Parkinson’s disease |