Metabolite aggregation in vivo

The paramount role metabolites play across different branches of life, as well as their part in various disorders, has been investigated for decades. Yet, only recently it has been revealed by our group that some of these life-essential building-blocks, including several amino acids and nucleobases, have the capacity to form cytotoxic amyloid-like structures, similar to those found in neurodegenerative disorders such as Alzheimer’s disease. This insight arises fundamental questions regarding the intrinsic mechanisms that must have evolved to maintain optimal levels of aggregation-prone metabolites. In addition, it offers new opportunities for diagnostics as well as therapy of a group of metabolic disorders resulting from mutations in genes encoding for metabolic enzymes and the corresponding metabolite substrate accumulation. Following the successful utilization of yeast for studying amyloid formation in living cells, we have recently established the first in vivo yeast model of adenine self-assembly using a strain blocked in the enzymatic pathway downstream to adenine. This model was found to be a valid system, as supported by its robust sensitivity to adenine, and by the fact that the adenine supramolecular structures could be detected both by an amyloid dye and an antibody specific for adenine assemblies. Furthermore, addition of generic fibrillation-modifying compounds rescued the toxic effect observed, indicating the therapeutic potential of our model. This powerful system is now used to gain insights concerning the intracellular molecular mechanisms that maintain metabolites in a soluble, non-aggregative, state as well as to study the pathophysiology that stands behind several genetic metabolic disorders.