Small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegans
| العنوان: | Small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegans |
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| المؤلفون: | Suneil K. Kalia, Omar M. A. El-Agnaf, Jarlath Byrne Rodgers, Aldis Krizus, Minesh Kapadia, Darren M O'Hara, Kazuko Fujisawa, Lorraine V. Kalia, Krystal Menezes, Joseph G. Culotti, Kevin S Chen, William S. Ryu, Susan Ping, Naomi P. Visanji, Hien Chau, Grishma Pawar, Satoshi Suo, Nour K. Majbour, Seiya Ishikura, Andres M. Lozano, Scott Spangler, Nhat Tran, Anna Cranston, Alix M. B. Lacoste, Shahin Khodaei, Connie Marras |
| المصدر: | Molecular Neurodegeneration Molecular Neurodegeneration, Vol 16, Iss 1, Pp 1-25 (2021) |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Artificial intelligence, Parkinson's disease, Dopamine, Motor Disorders, chemistry.chemical_compound, 0302 clinical medicine, Caenorhabditis elegans, Mammals, 0303 health sciences, education.field_of_study, biology, Drug discovery, Dopaminergic, Neurodegeneration, 3. Good health, Research Article, medicine.drug, Population, Alpha-synuclein, 03 medical and health sciences, Cellular and Molecular Neuroscience, In vivo, Machine learning, medicine, Animals, Animal model, RC346-429, education, Molecular Biology, 030304 developmental biology, Dopaminergic Neurons, Natural language processing, RC952-954.6, biology.organism_classification, medicine.disease, Rats, Disease Models, Animal, nervous system, chemistry, Geriatrics, Oligomers, Parkinson’s disease, Neurology. Diseases of the nervous system, Neurology (clinical), Neuroscience, 030217 neurology & neurosurgery |
| الوصف: | 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. |
| تدمد: | 1750-1326 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d87a11cbb70df9392264f3dcb3df5afd https://doi.org/10.1186/s13024-021-00497-6 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....d87a11cbb70df9392264f3dcb3df5afd |
| قاعدة البيانات: | OpenAIRE |
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