Toward next-generation therapeutics for AD and tauopathies through disease mechanism-informed drug screens
University of Toronto; University of California, San Francisco
Neurodegenerative diseases of aging such as Alzheimer’s disease pose a major health challenge in the 21st century. Our research builds on the hypothesis that the most promising early diagnostics and disease intervention strategies will emerge from an in-depth understanding of disease etiologies and the next-generation drug screens whose designs are informed by insights gained into the causes of proteotoxicity that underlie the disease. The project will thus investigate at different angles how the proteotoxic stress at the systems biology level leads to neurodegeneration observed in diseases such as Alzheimer’s and prion diseases. This will be followed by the identification of disease-related perturbed interactions of key molecules like tau and prion proteins. The insights will help in the design and implementation of cell-based screens of drug-like small molecules to counteract the molecular pathways that lead to toxicity and neurodegeneration.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
This project aims to combine discovery-based approaches exploring the neuro-toxicity of such diseases with the large-scale small-molecule drug screens. Thus, the discovery components of the project will add value to the drug screen (i) by informing the design of relevant cell-based screens, and (ii) by narrowing the search space of small molecule compounds to a manageable scope. The unbiased investigation of key molecular events involved in these diseases will provide novel angles for therapeutics development that will make such efforts more directed towards promising and effective drug targets.
It is hoped that knowledge gained from the first phase of this research be implemented into drug development strategies that can improve the toxicity phenotypes observed in the relevant models and thus accelerate the search for an effective therapy for these diseases. This collaboration will build on the big data systems biology research and valuable new expertise in the design and execution of screens of drug-like small molecules, which is available in the host laboratory with an eminent worldwide track-record in high-throughput small molecule screens for diseases like Alzheimer’s and prion diseases.
This research program aimed to identify molecular perturbations resulting from aggregation of the protein tau in a class of neurodegenerative diseases called tauopathies. Thus far, we have successfully developed cellular models that recapitulate the aggregation of tau from multiple patients with progressive supranuclear palsy (PSP).We have explored the changes in protein expression and modifications relevant to disease. Future work based on the findings of this research will be expanded to other tauopathies, including Pick’s and Alzheimer’s diseases, and will explore how they differ from PSP at the molecular level. These results will inform mechanism-driven drug discovery to develop compounds that specifically target tau aggregation in each tauopathy. Additionally, we have developed a second cellular model that recapitulates tau aggregation, which will complement ongoing drug discovery efforts.