Small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegans

Abstract Background 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...

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Autores principales:	Kevin S. Chen, Krystal Menezes, Jarlath B. Rodgers, Darren M. O’Hara, Nhat Tran, Kazuko Fujisawa, Seiya Ishikura, Shahin Khodaei, Hien Chau, Anna Cranston, Minesh Kapadia, Grishma Pawar, Susan Ping, Aldis Krizus, Alix Lacoste, Scott Spangler, Naomi P. Visanji, Connie Marras, Nour K. Majbour, Omar M. A. El-Agnaf, Andres M. Lozano, Joseph Culotti, Satoshi Suo, William S. Ryu, Suneil K. Kalia, Lorraine V. Kalia
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Alpha-synuclein Animal model Artificial intelligence Drug discovery Machine learning Natural language processing Neurology. Diseases of the nervous system RC346-429 Geriatrics RC952-954.6
Acceso en línea:	https://doaj.org/article/1a816ab50aad45a9bf006d7c91b18cff
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spelling	oai:doaj.org-article:1a816ab50aad45a9bf006d7c91b18cff2021-11-14T12:16:05ZSmall molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegans10.1186/s13024-021-00497-61750-1326https://doaj.org/article/1a816ab50aad45a9bf006d7c91b18cff2021-11-01T00:00:00Zhttps://doi.org/10.1186/s13024-021-00497-6https://doaj.org/toc/1750-1326Abstract Background 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. Methods 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. Results 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. Conclusions 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.Kevin S. ChenKrystal MenezesJarlath B. RodgersDarren M. O’HaraNhat TranKazuko FujisawaSeiya IshikuraShahin KhodaeiHien ChauAnna CranstonMinesh KapadiaGrishma PawarSusan PingAldis KrizusAlix LacosteScott SpanglerNaomi P. VisanjiConnie MarrasNour K. MajbourOmar M. A. El-AgnafAndres M. LozanoJoseph CulottiSatoshi SuoWilliam S. RyuSuneil K. KaliaLorraine V. KaliaBMCarticleAlpha-synucleinAnimal modelArtificial intelligenceDrug discoveryMachine learningNatural language processingNeurology. Diseases of the nervous systemRC346-429GeriatricsRC952-954.6ENMolecular Neurodegeneration, Vol 16, Iss 1, Pp 1-25 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Alpha-synuclein Animal model Artificial intelligence Drug discovery Machine learning Natural language processing Neurology. Diseases of the nervous system RC346-429 Geriatrics RC952-954.6
spellingShingle	Alpha-synuclein Animal model Artificial intelligence Drug discovery Machine learning Natural language processing Neurology. Diseases of the nervous system RC346-429 Geriatrics RC952-954.6 Kevin S. Chen Krystal Menezes Jarlath B. Rodgers Darren M. O’Hara Nhat Tran Kazuko Fujisawa Seiya Ishikura Shahin Khodaei Hien Chau Anna Cranston Minesh Kapadia Grishma Pawar Susan Ping Aldis Krizus Alix Lacoste Scott Spangler Naomi P. Visanji Connie Marras Nour K. Majbour Omar M. A. El-Agnaf Andres M. Lozano Joseph Culotti Satoshi Suo William S. Ryu Suneil K. Kalia Lorraine V. Kalia Small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegans
description	Abstract Background 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. Methods 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. Results 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. Conclusions 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.
format	article
author	Kevin S. Chen Krystal Menezes Jarlath B. Rodgers Darren M. O’Hara Nhat Tran Kazuko Fujisawa Seiya Ishikura Shahin Khodaei Hien Chau Anna Cranston Minesh Kapadia Grishma Pawar Susan Ping Aldis Krizus Alix Lacoste Scott Spangler Naomi P. Visanji Connie Marras Nour K. Majbour Omar M. A. El-Agnaf Andres M. Lozano Joseph Culotti Satoshi Suo William S. Ryu Suneil K. Kalia Lorraine V. Kalia
author_facet	Kevin S. Chen Krystal Menezes Jarlath B. Rodgers Darren M. O’Hara Nhat Tran Kazuko Fujisawa Seiya Ishikura Shahin Khodaei Hien Chau Anna Cranston Minesh Kapadia Grishma Pawar Susan Ping Aldis Krizus Alix Lacoste Scott Spangler Naomi P. Visanji Connie Marras Nour K. Majbour Omar M. A. El-Agnaf Andres M. Lozano Joseph Culotti Satoshi Suo William S. Ryu Suneil K. Kalia Lorraine V. Kalia
author_sort	Kevin S. Chen
title	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_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_sort	small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in c. elegans
publisher	BMC
publishDate	2021
url	https://doaj.org/article/1a816ab50aad45a9bf006d7c91b18cff
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Small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegans

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