Assembly of Branched Chain Amino Acids to Toxic Fibrils may be Related to Pathogenesis of Maple Syrup Urine Disease

Inborn errors of metabolisms (IEMs) are group of diseases caused by mutations in single genes, leading to buildup of metabolites, toxic or disrupt normal cellular function. The etiological relation of metabolic disorders has been uncovered through study of metabolite amyloids. Various metabolites that accumulate in IEMs have been reported to self-assemble into organized structures. These structures exhibit similar physicochemical properties as proteinaceous amyloid fibrils. Our study illustrates the aggregation properties of branched chain amino acids (BCAAs), isoleucine, leucine, and valine that accumulate in maple syrup urine disease (MSUD) to investigate their propensities to assemble into amyloid-like fibrils. The structural morphologies of BCAAs are studied via microscopic techniques. Further, characterization techniques are employed to understand the physicochemical properties of the self-assemblies and their underlying mechanism. The amyloid-like nature of these aggregates is confirmed using thioflavin T and congo red assays. The (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay reveals BCAAs are cytotoxic and significantly decrease cell viability. This study plays a key role in understanding the physicochemical properties of MSUD in the context of amyloid diseases, possibly paving the way for the development of its therapeutic solutions in the future.