A novel approach for identification of therapeutic leads to the Maple Syrup Urine Disease

Awardee: Ehud Gazit

Institution: Tel Aviv University

Awarded Amount: $44,037

Final Report Summary:

We have recently shown that metabolites, as simple as single amino acids and nucleobases, can form amyloid-like structures, thus providing a novel paradigm for inborn error of metabolism (IEM) disorders. Here, we wish to explore a never-tested hypothesis suggesting that the systemic pathology following branched-chain amino acids (BCAAs) abnormally high levels in the blood, serum and urine of Maple Syrup Urine Disease (MSUD) patients may be related to the formation of amyloid-like structures. Our preliminary data provide a proof-of-concept for this hypothesis, indicating that BCAAs can form unique assemblies with amyloid-like characteristics. Therefore, we postulate that high levels of BCAAs can lead to the formation of toxic structures that in turn can be involved in the cytotoxicity observed in the disorder. This discovery can offer new prospects for understanding the complex etiologies of the disease and finding the proper treatment for MSUD patients. Here, we set out to utilize our unique expertise and knowledge in metabolite self-assembly and yeast models for IEMs to address fundamental issues concerning MSUD and for the identification of therapeutic leads.

In the scope of the MDBR project, we were able to successfully establish a unicellular yeast model as well as a multicellular organism nematode model for MSUD. Our data indicate that the MSUD models are sensitive to isoleucine supplied in the growth medium, implying the involvement of isoleucine accumulation and self-assembly in cell toxicity and the pathology of MSUD.

Our yeast model was successfully used as a platform for high throughput phenotypic screening of potential therapeutic agents to target metabolite aggregation. Compounds found to suppress the toxicity conferred by isoleucine feeding of the mutant strain in the screen were further characterized and validated in the yeast system. Yet, the compounds that were identified in the selected screen did not show a significant effect in the nematode model and the neuroblastoma cells and therefore could not be used as a potential treatment. Nevertheless, our successful pilot screen proves the strength of our platform and its future potential for the identification of novel treatment for MSUD patients.