國家衛生研究院 NHRI:Item 3990099045/12841
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    題名: Loss of the Drosophila branched-chain alpha-ketoacid dehydrogenase complex results in neuronal dysfunction
    其他題名: Loss of the Drosophila branched-chain α-ketoacid dehydrogenase complex results in neuronal dysfunction
    作者: Tsai, HY;Wu, SC;Li, JC;Chen, YM;Chan, CC;Chen, CH
    貢獻者: National Institute of Infectious Diseases and Vaccinology;National Mosquito-Borne Diseases Control Research Center
    摘要: 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 keto-acid dehydrogenase (BCKDH) enzyme, 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 Drosophila model of MSUD by knocking out the dDBT gene, an ortholog of the human dihydrolipoamide branched chain transacylase (DBT) subunit of BCKDH. The homozygous dDBT mutant larvae recapitulate an array of MSUD phenotypes, including aberrant BCAA accumulation, developmental defects, poor mobile behavior, and disrupted L-glutamate homeostasis. Moreover, the dDBT mutation causes neuronal apoptosis during the developmental progression of larval brains. The genetic and functional evidence generated by in vivo depletion of dDBT expression in the eye shows severe impairment of retinal rhadomeres. Further, the dDBT mutant shows elevated oxidative stress and higher lipid peroxidation accumulation in the larval brain. Therefore we conclude from in vivo evidence that the loss of dDBT results in oxidative brain damage that may led to neuronal cell death and contribute to aspects of MSUD pathology. Importantly, when the dDBT mutants were administrated with Metformin, the aberrances in BCAA levels and motor behavior were ameliorated. This intriguing outcome strongly merits the use of the dDBT mutant as a platform for developing MSUD therapies.
    日期: 2020-08-27
    關聯: Disease Models and Mechanisms. 2020 Aug 27;13(8):Article number dmm044750.
    Link to: http://dx.doi.org/10.1242/dmm.044750
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1754-8403&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000567471400004
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85090035290
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