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

Molecular Neurodegeneration

Alix Lacoste¹  Jarlath B. Rodgers²  Shahin Khodaei²  William S. Ryu³  Naomi P. Visanji⁴  Connie Marras⁵  Scott Spangler⁶  Susan Ping⁷  Kazuko Fujisawa⁷  Kevin S. Chen⁷  Krystal Menezes⁷  Seiya Ishikura⁷  Aldis Krizus⁷  Grishma Pawar⁷  Anna Cranston⁷  Minesh Kapadia⁷  Darren M. O’Hara⁷  Hien Chau⁷  Nhat Tran⁷  Andres M. Lozano⁸  Suneil K. Kalia⁹  Lorraine V. Kalia^1,10  Joseph Culotti^1,11  Satoshi Suo^1,12  Nour K. Majbour^1,13  Omar M. A. El-Agnaf^1,13 

[1] BenevolentAI, New York, NY, USA;Donnelly Centre, University of Toronto, Toronto, ON, Canada;Donnelly Centre, University of Toronto, Toronto, ON, Canada;Department of Physics, University of Toronto, Toronto, ON, Canada;Edmond J. Safra Program in Parkinson’s Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Division of Neurology, Department of Medicine, Toronto Western Hospital, University Health Network, Toronto, ON, Canada;Edmond J. Safra Program in Parkinson’s Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Division of Neurology, Department of Medicine, Toronto Western Hospital, University Health Network, Toronto, ON, Canada;Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada;IBM Research-Almaden, San Jose, CA, USA;Krembil Brain Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada;Krembil Brain Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada;Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada;Krembil Brain Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada;Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada;KITE and CRANIA, University Health Network, Toronto, ON, Canada;Krembil Brain Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada;Edmond J. Safra Program in Parkinson’s Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Division of Neurology, Department of Medicine, Toronto Western Hospital, University Health Network, Toronto, ON, Canada;Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada;Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada;Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada;Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada;Department of Pharmacology, Faculty of Medicine, Saitama Medical University, Saitama, Japan;Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar;

关键词: Alpha-synuclein;    Animal model;    Artificial intelligence;    Drug discovery;    Machine learning;    Natural language processing;    Neurodegeneration;    Oligomers;    Parkinson’s disease;   

DOI  :  10.1186/s13024-021-00497-6

来源: Springer

【 摘 要 】

BackgroundParkinson’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.MethodsTo 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.ResultsWe 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.ConclusionsWe 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.

【 授权许可】

CC BY