Cargando…
Loss of the Drosophila 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-rest...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Company of Biologists Ltd
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473638/ https://www.ncbi.nlm.nih.gov/pubmed/32680850 http://dx.doi.org/10.1242/dmm.044750 |
_version_ | 1783579216649912320 |
---|---|
author | Tsai, Hui-Ying Wu, Shih-Cheng Li, Jian-Chiuan Chen, Yu-Min Chan, Chih-Chiang Chen, Chun-Hong |
author_facet | Tsai, Hui-Ying Wu, Shih-Cheng Li, Jian-Chiuan Chen, Yu-Min Chan, Chih-Chiang Chen, Chun-Hong |
author_sort | Tsai, Hui-Ying |
collection | PubMed |
description | 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 Drosophila model of MSUD by knocking out the dDBT gene, an ortholog of the human gene encoding the 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 indicates severe impairment of retinal rhabdomeres. 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 lead 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. This article has an associated First Person interview with the joint first authors of the paper. |
format | Online Article Text |
id | pubmed-7473638 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | The Company of Biologists Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-74736382020-09-08 Loss of the Drosophila branched-chain α-ketoacid dehydrogenase complex results in neuronal dysfunction Tsai, Hui-Ying Wu, Shih-Cheng Li, Jian-Chiuan Chen, Yu-Min Chan, Chih-Chiang Chen, Chun-Hong Dis Model Mech Research Article 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 Drosophila model of MSUD by knocking out the dDBT gene, an ortholog of the human gene encoding the 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 indicates severe impairment of retinal rhabdomeres. 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 lead 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. This article has an associated First Person interview with the joint first authors of the paper. The Company of Biologists Ltd 2020-08-27 /pmc/articles/PMC7473638/ /pubmed/32680850 http://dx.doi.org/10.1242/dmm.044750 Text en © 2020. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/4.0This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
spellingShingle | Research Article Tsai, Hui-Ying Wu, Shih-Cheng Li, Jian-Chiuan Chen, Yu-Min Chan, Chih-Chiang Chen, Chun-Hong Loss of the Drosophila branched-chain α-ketoacid dehydrogenase complex results in neuronal dysfunction |
title | Loss of the Drosophila branched-chain α-ketoacid dehydrogenase complex results in neuronal dysfunction |
title_full | Loss of the Drosophila branched-chain α-ketoacid dehydrogenase complex results in neuronal dysfunction |
title_fullStr | Loss of the Drosophila branched-chain α-ketoacid dehydrogenase complex results in neuronal dysfunction |
title_full_unstemmed | Loss of the Drosophila branched-chain α-ketoacid dehydrogenase complex results in neuronal dysfunction |
title_short | Loss of the Drosophila branched-chain α-ketoacid dehydrogenase complex results in neuronal dysfunction |
title_sort | loss of the drosophila branched-chain α-ketoacid dehydrogenase complex results in neuronal dysfunction |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473638/ https://www.ncbi.nlm.nih.gov/pubmed/32680850 http://dx.doi.org/10.1242/dmm.044750 |
work_keys_str_mv | AT tsaihuiying lossofthedrosophilabranchedchainaketoaciddehydrogenasecomplexresultsinneuronaldysfunction AT wushihcheng lossofthedrosophilabranchedchainaketoaciddehydrogenasecomplexresultsinneuronaldysfunction AT lijianchiuan lossofthedrosophilabranchedchainaketoaciddehydrogenasecomplexresultsinneuronaldysfunction AT chenyumin lossofthedrosophilabranchedchainaketoaciddehydrogenasecomplexresultsinneuronaldysfunction AT chanchihchiang lossofthedrosophilabranchedchainaketoaciddehydrogenasecomplexresultsinneuronaldysfunction AT chenchunhong lossofthedrosophilabranchedchainaketoaciddehydrogenasecomplexresultsinneuronaldysfunction |