A yeast model of metabolic disorders

A yeast model of metabolic disorders

There are hundreds of metabolic disorders -- including phenylketonuria, tyrosinemia, maple syrup urine disease and homocystinuria. These disorders lead to congenital diseases that produce a critical enzyme deficiency that interferes with the body's metabolism. The pathologies and symptoms vary among the diseases, but all of them are usually fatal and have no known cure. Most metabolic disorders affect infants.

The majority of these diseases currently lack effective treatments and patients must maintain a strict diet, avoiding certain food items that contain substances their bodies cannot break down. Often the proposed solutions, such as bone marrow transplants, are extremely expensive and only partially effective.

A new study suggests that the role of yeast, the world's most basic eukaryotic unicellular organism, may pave the way for the development of novel, more effective therapies. The research was published in Nature Communications.

The research is based on previous studies that revealed the role of toxic metabolite accumulation in the pathology of metabolic disorders. "We have known for a while now that amyloids are linked to severe diseases of the central nervous system, such as Alzheimer's, Parkinson's and Huntington's," the senior author says. "Recent experiments conducted in our lab have shown that they characterize genetic metabolic disorders as well. In such disorders, the gene responsible for producing an enzyme, which modifies a particular metabolite, is impaired.

"As a result, large quantities of that metabolite accumulate in the body and cause serious damage," the author continues. "While each condition is separately considered as 'rare,' these disorders constitute a major proportion of pediatric genetic diseases."

In the new study, the team genetically manipulated yeast cells to produce a toxic accumulation of the metabolite adenine, devising the first in vivo yeast model of a congenital metabolic disease as a result. The innovative platform will allow scientists to screen thousands of drug-like small molecules to identify molecules that could lead to novel therapies.

Using a strain blocked in the enzymatic pathway downstream to adenine, the authors observed a non-linear dose-dependent growth inhibition. Both the staining with an indicative amyloid dye and anti-adenine assemblies antibodies demonstrated the accumulation of adenine amyloid-like structures, which were eliminated by lowering the supplied adenine levels.

 Treatment with a polyphenol inhibitor reduced the occurrence of amyloid-like structures while not affecting the dramatic increase in intracellular adenine concentration, resulting in inhibition of cytotoxicity, further supporting the notion that toxicity is triggered by adenine assemblies.

"If you can successfully connect the pieces of the puzzle, then you can understand the biology behind a disease," the author concludes. "It is critically important to understand the pathways leading to the toxicity caused by metabolite accumulations in order to develop the appropriate therapy. In this case, the lives of thousands of children may be saved and their quality of life significantly improved."