BDK Deficiency in Cerebral Cortex Neurons Causes Neurological Abnormalities and Affects Endurance Capacity.

Anna Mizusawa,Yoshiharu Shimomura,Yasuyuki Kitaura,Rina Kamei,Minori Yamada,Ayako Watanabe

doi:10.3390/nu12082267

Anna Mizusawa, Yoshiharu Shimomura + Show 4 more

Open Access

https://doi.org/10.3390/nu12082267

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Journal: Nutrients	Publication Date: Jul 29, 2020
Citations: 5	License type: CC BY 4.0

Affiliation: Chubu University, Nagoya University

Abstract

Branched-chain amino acid (BCAA) catabolism is regulated by its rate-limiting enzyme, branched-chain α-keto acid dehydrogenase (BCKDH), which is negatively regulated by BCKDH kinase (BDK). Loss of BDK function in mice and humans leads to dysregulated BCAA catabolism accompanied by neurological symptoms such as autism; however, which tissues or cell types are responsible for the phenotype has not been determined. Since BDK is highly expressed in neurons compared to astrocytes, we hypothesized that neurons are the cell type responsible for determining the neurological features of BDK deficiency. To test this hypothesis, we generated mice in which BDK deletion is restricted to neurons of the cerebral cortex (BDKEmx1-KO mice). Although BDKEmx1-KO mice were born and grew up normally, they showed clasped hind limbs when held by the tail and lower brain BCAA concentrations compared to control mice. Furthermore, these mice showed a marked increase in endurance capacity after training compared to control mice. We conclude that BDK in neurons of the cerebral cortex is essential for maintaining normal neurological functions in mice, and that accelerated BCAA catabolism in that region may enhance performance in running endurance following training.

Highlights

Leucine, valine, and isoleucine are branched-chain amino acids (BCAAs) and are considered essential amino acids for mammals
Free BCAAs are used as building blocks in protein synthesis as well as energy sources and nitrogen donors to BCAA catabolic enzymes
BCAAs are transported into the brain through the blood–brain barrier, mostly using system L1 and to a lesser

Summary

Introduction

Valine, and isoleucine are branched-chain amino acids (BCAAs) and are considered essential amino acids for mammals. BCAAs exist as free amino acids and are abundant in proteins, providing approximately 35% of essential amino acids in indispensable muscle proteins [1]. Free BCAAs are used as building blocks in protein synthesis as well as energy sources and nitrogen donors to BCAA catabolic enzymes. One of the most well-known signaling functions is stimulation of protein synthesis via the mammalian target of rapamycin complex (mTORC1) with hormonal signals [3]. Metabolism of BCAAs plays notable roles in the brain by directly or indirectly providing essential nutrients as well as serving as components of neurotransmitters, for example, glutamate or amine neurotransmitters including 5-hydroxytryptamine known as monoamine serotonin [4]. BCAAs are transported into the brain through the blood–brain barrier, mostly using system L1 and to a lesser

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