Branched-Chain Amino Acids in Parkinson's Disease: Molecular Mechanisms and Therapeutic Potential

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra, resulting in motor symptoms such as bradykinesia, tremor, rigidity, and postural instability, as well as a wide variety of non-motor manifestations. Branched-chain amino acids (BCAAs)-leucine, isoleucine, and valine-are essential nutrients involved in neurotransmitter synthesis, energy metabolism, and cellular signaling. Emerging evidence suggests that BCAA metabolism is intricately linked to the pathophysiology of PD. Dysregulation of BCAA levels has been associated with energy metabolism, mitochondrial dysfunction, oxidative stress, neuroinflammation, and altered neurotransmission. Furthermore, the branched-chain ketoacid dehydrogenase kinase (BCKDK), a key regulator of BCAA catabolism, has been implicated in PD through its role in modulating neuronal energetics and redox homeostasis. In this review, we synthesize current molecular, genetic, microbiome, and clinical evidence on BCAA dysregulation in PD to provide an integrative perspective on the BCAA-PD axis and highlight directions for future translational research. We explored the dualistic role of BCAAs as both potential neuroprotective agents and metabolic stressors, and critically examined the therapeutic prospects and limitations of BCAA supplementation and BCKDK targeting.

Keywords: Parkinson’s disease; amino acid metabolism; branched-chain amino acids (BCAAs); branched-chain ketoacid dehydrogenase kinase (BCKDK); gut–brain axis; mitochondrial dysfunction; neuroinflammation; precision therapeutics.

Figure 1

Dual neurotoxic consequences of BCKDK dysregulation in Parkinson’s disease. The schematic illustrates the bidirectional pathogenic effects of altered branched-chain α-keto acid dehydrogenase kinase (BCKDK) activity in Parkinson’s disease (PD). In the right panel (BCKDK gain-of-function), increased BCKDK activity inhibits the BCKDH complex, leading to the accumulation of branched-chain α-keto acids (BCKAs: KIC, KMV, KIV). Elevated BCKAs promote mitochondrial dysfunction, reactive oxygen species (ROS) production, glutamate excitotoxicity via N-methyl-D-aspartate (NMDA) receptor overactivation, and microglial activation, ultimately contributing to dopaminergic neurodegeneration. In the left panel (BCKDK loss-of-function), reduced BCKDK activity causes excessive branched-chain amino acid (BCAA; leucine, isoleucine, valine) catabolism and systemic BCAA depletion. This impairs neurotransmitter synthesis by disrupting the BCAT–glutamate–glutamine axis, resulting in synaptic dysfunction, bradykinesia, and cognitive decline. The figure highlights the central role of the BCKDK–BCKDH axis in regulating mitochondrial function, oxidative balance, and neurotransmitter homeostasis in PD pathophysiology.

Figure 2

Targeting BCAA metabolism in Parkinson’s disease. This figure illustrates the key sites of BCAA-related dysregulation and therapeutic intervention along the microbiota–BCAA–brain axis in Parkinson’s disease. Strategies such as nutritional supplementation, BCKDK inhibition, and gut microbiota modulation aim to restore metabolic balance. These approaches may enhance L-DOPA availability, improve mitochondrial function, and reduce oxidative stress and neuroinflammation.