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Generation of Branched chain α‐keto acid dehydrogenase enzyme complex E1α knockout mouse models

The goal of this study was to generate murine models for Maple Syrup Urine Disease (MSUD), enabling elucidation of the biochemical basis for the pathology of this inborn error of branched chain amino acid (BCAA) metabolism. As expected, loss of the E1α subunit (E1α KO) of the E1 dehydrogenase enzyme resulted in a mouse that died 24hr after birth. KO pups showed elevated levels of BCAA and branched chain α‐keto acids (BCKA) in their plasma and body tissues. The heterozygote mice (Het) were viable with ~50% of E1 enzyme levels found in wild type (WT) mouse tissues. When fed a 60% protein diet (HPD), Het food intake was lower, whereas body weight, percent fat, and plasma BCAAs were significantly higher than WT mice. To determine if deletion of E1 in brain could reproduce the MSUD brain pathology, a neuronal E1α KO was generated using the nestin‐Cre promoter (Nes‐E1α KO). These mice did not exhibit an MSUD phenotype even though E1 enzyme protein was also lowered in tissues outside the brain. The Nes‐E1α KO mice were sensitive to a HPD exhibiting higher percent of body fat elevated plasma BCAA and BCKA and food aversion. The data suggest that BCAA and/or BCKA may play a role in food intake and fat metabolism. Elevated peripheral BCAA and BCKA are also required to induce the MSUD brain pathology. (Funding: Virginia Tech)