Amyotrophic lateral sclerosis (ALS, motor neuron or Lou Gehrig's disease) and frontotemporal lobar degeneration (FTLD) are fatal neurodegenerative disorders that are associated with the neural aggregation of specific proteins. Recently, the DNA/RNA-binding proteins FUS (Fused in Sarcoma) and TDP-43 (TAR DNA-binding protein) were implicated in these diseases. Just as mutations in superoxide dismutase-1 (SOD1) were previously linked to some familial forms of ALS, mutations in the genes that code FUS and TDP-43 have likewise been linked to familial ALS. However and perhaps more importantly, wild-type FUS and TDP-43 have also been identified as key components of the neuronal ubiquitinated cytosolic inclusions in cases of sporadic ALS, which accounts for 85-90% of all ALS cases. The finding that these two proteins are so intimately linked to ALS and FTLD neurodegeneration shifts the paradigm in our understanding of the mechanisms that underlie these diseases. And yet, exactly how protein aggregation leads to neuronal cell death is unknown, hampering the development of effective treatment strategies. We recently developed a yeast model for studying FUS aggregation and toxicity that recapitulates observations made in diseased neurons. The over-expression and concomitant aggregation of FUS is cytotoxic and causes severe inhibition of cell growth, offering a mechanism for performing high-throughput screens of genetic and chemical modifiers of toxicity. We plan to use the chemical library screening offered through the Molecular Libraries Probe Production Centers Network (MLPCN) to identify small molecules that can ameliorate FUS-induced toxicity. Promising candidates will be confirmed in laboratory-scale experiments and will be further validated in an animal FUS-toxicity model. Additionally, drug candidates will be cross-tested in other established neurodegenerative disease-related yeast models. Our system offers a fast and inexpensive screening mechanism to find drug leads that may eventually be developed into therapeutics capable of reducing the neurodegeneration in ALS, FTLD and other disorders.

Public Health Relevance

This project is dedicated to the identification of drugs that have therapeutic potential for FUS proteinopathy diseases, such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). This project employs the tractable eukaryote Saccharomyces cerevisiae for very high-throughput chemical library screens, which are then followed by validation in mammalian cell culture and in a Drosophila animal model. This strategy will provide an inexpensive and efficient approach for searching for drug candidates for neurodegenerative diseases in general, and ALS and FTLD specifically.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Small Research Grants (R03)
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Special Emphasis Panel (ZRG1-BST-F (50))
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Singh, Hari
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Henry M. Jackson Fdn for the Adv Mil/Med
United States
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Kryndushkin, Dmitry; Pripuzova, Natalia; Burnett, Barrington G et al. (2013) Non-targeted identification of prions and amyloid-forming proteins from yeast and mammalian cells. J Biol Chem 288:27100-11