Brain Branched-Chain Amino Acids in Maple Syrup Urine Disease: Implications for Neurological Disorders

Abstract

Maple syrup urine disease (MSUD) is an autosomal recessive disorder caused by decreased activity of the branched-chain α-ketoacid dehydrogenase complex (BCKDC), which catalyzes the irreversible catabolism of branched-chain amino acids (BCAAs). Current management of this BCAA dyshomeostasis consists of dietary restriction of BCAAs and liver transplantation, which aims to partially restore functional BCKDC activity in the periphery. These treatments improve the circulating levels of BCAAs and significantly increase survival rates in MSUD patients. However, significant cognitive and psychiatric morbidities remain. Specifically, patients are at a higher lifetime risk for cognitive impairments, mood and anxiety disorders (depression, anxiety, and panic disorder), and attention deficit disorder. Recent literature suggests that the neurological sequelae may be due to the brain-specific roles of BCAAs. This review will focus on the derangements of BCAAs observed in the brain of MSUD patients and will explore the potential mechanisms driving neurologic dysfunction. Finally, we will discuss recent evidence that implicates the relevance of BCAA metabolism in other neurological disorders. An understanding of the role of BCAAs in the central nervous system may facilitate future identification of novel therapeutic approaches in MSUD and a broad range of neurological disorders.

Branched-chain amino acids govern the high learning ability phenotype in Tokai high avoider (THA) rats

“…S2 online), we compared THA rats with Wistar rats, which had no other phenotypic differences. As expected, while the expression of BCAT1, a peripheral nervous system-specific isoform 22 , 23 , was increased, that of BCKDK and the phosphorylation levels of BCKDHA were lower in the hippocampi of THA rats compared to Wistar rats (Fig. 2 b).…”

Metabolism of Amino Acids in Cancer

“…Moreover, suppression of BCAA catabolic enzyme expression led to reduced cell proliferation and BCAA accumulation in liver carcinogenesis but not in regenerating liver tissues (Ericksen et al, 2019 ). BCKAs can be metabolized by BCKDH to branched-chain acyl-CoA, and blocking this step causes serious metabolic disorders, such as maple syrup urine disease (Xu et al, 2020 ) and propionic academia (Chen et al, 2017 ). Branched-chain acyl-CoA can be further metabolized in several steps to the TCA cycle, and intermediates, such as acetyl-CoA and/or succinyl-CoA, can be used for energy production (She et al, 2007 ) or acetylation modification (Campbell and Wellen, 2018 ).…”

Metabolite Changes in the Aqueous Humor of Patients With Retinal Vein Occlusion Macular Edema: A Metabolomics Analysis

“…Many studies had also confirmed that this metabolic pathway was abnormal in a variety of diseases, like diabetic kidney disease ( Tao et al, 2020 ), neurodegeneration ( Zizioli et al, 2015 ), Vogt–Koyanagi–Harada ( Xu et al, 2021 ), et al Valine, leucine, and isoleucine, namely, branched-chain amino acids (BCAAs), which could over-induce oxidative processes and up-regulate proinflammatory factors ( Zhenyukh et al, 2017 ), are unable to be synthesized by animals. Hence, a variety of pathological changes, such as maple syrup urine disease (MSUD) ( Xu et al, 2020 ), type 2 diabetes ( Zeng et al, 2019 ), and cancer ( Peng et al, 2020 ; Sivanand and Vander Heiden, 2020 ) could be detected when there is a disorder in BCAA metabolism. Nevertheless, the molecular mechanisms of BCAAs involved in the pathogenesis of RVO-ME-inducing retinopathy remain unknown, thus warranting future research.…”