Loss of the branched-chain α-ketoacid dehydrogenase complex results in neuronal dysfunction.

Maple syrup urine disease (MSUD) is an inherited error in the metabolism of branched-chain amino acids (BCAAs) caused by a severe deficiency of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which ultimately leads to neurological disorders. The limited therapies, including protein-restricted diets and liver transplants, are not as effective as they could be for the treatment of MSUD due to the current lack of molecular insights into the disease pathogenesis. To address this issue, we developed a model of MSUD by knocking out the gene, an ortholog of the human gene encoding the dihydrolipoamide branched chain transacylase (DBT) subunit of BCKDH. The homozygous mutant larvae recapitulate an array of MSUD phenotypes, including aberrant BCAA accumulation, developmental defects, poor mobile behavior and disrupted L-glutamate homeostasis. Moreover, the mutation causes neuronal apoptosis during the developmental progression of larval brains. The genetic and functional evidence generated by depletion of expression in the eye indicates severe impairment of retinal rhabdomeres. Further, the mutant shows elevated oxidative stress and higher lipid peroxidation accumulation in the larval brain. Therefore, we conclude from evidence that the loss of results in oxidative brain damage that may lead to neuronal cell death and contribute to aspects of MSUD pathology. Importantly, when the mutants were administrated with Metformin, the aberrances in BCAA levels and motor behavior were ameliorated. This intriguing outcome strongly merits the use of the mutant as a platform for developing MSUD therapies.This article has an associated First Person interview with the joint first authors of the paper.