Unlocking Parkinson’s disease: harnessing the untapped potential of fatty acid metabolism in disease pathogenesis

Figures

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  Figure 1. Classification and representative structures of fatty acids. Fatty acids are categorized as saturated fatty acids (SFAs) or unsaturated fatty acids (USFAs). SFAs, which lack double bonds, are grouped by chain length (short-, medium-, long-chain; exemplified by valeric, lauric, and palmitic acid, respectively). USFAs contain one or more double bonds and include monounsaturated (MUFAs; oleic acid, ω-9) and polyunsaturated [PUFAs; docosahexaenoic acid (DHA, ω-3) and linoleic acid (LA, ω-6)] forms. Representative chemical structures for each subclass are shown. Created with Adobe Illustrator 2020.

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  Figure 2. Neuron–astrocyte coupling in fatty acid metabolism. Neurons assimilate circulating FAs through the FATP/CD36 pathway, facilitating their mitochondrial β-oxidation to produce ATP, while concurrently generating ROS. Surplus or oxidized FAs are transported to astrocytes via lipid particles containing ABCA1-APOE. Astrocytes internalize these lipid particles through LRP1/LDLR receptors, subsequently storing them in LDs. Within astrocytes, FAs are processed via β-oxidation to generate ATP or are converted into ketone bodies (β-hydroxybutyrate, acetoacetate) to supply energy to neurons. Additionally, the peroxisomal metabolism of very-long-chain FAs and the desaturation process mediated by SCD1 in neurons are illustrated, emphasizing the role of this metabolic coupling in mitigating lipotoxicity and enhancing neuronal bioenergetics. Created with Adobe Illustrator 2020.

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  Figure 3. Dysregulation of fatty acid metabolism in PD pathogenesis. This schematic depicts how altered FA metabolism contributes to PD progression, spanning systemic and brain-intrinsic mechanisms. In the periphery, gut dysbiosis leads to abnormal short-chain FAs (SCFAs) and impaired blood–brain barrier (BBB) integrity, driving altered FA uptake into the brain. In neurons, increased CD36-mediated SCFA uptake and dysregulated β-oxidation promote mitochondrial dysfunction, reactive oxygen species (ROS) production, and lipid peroxidation, exacerbating α-synuclein misfolding, Lewy body formation, and ferroptosis. De novo FA synthesis is upregulated via ACLY, ACC, and FASN, increasing saturated (SFAs) and unsaturated (PUFAs/MUFAs) FA pools, while reduced CPT1 activity impairs mitochondrial FA import. In astrocytes, impaired lipid droplet turnover, calcium dyshomeostasis, and reduced β-oxidation disrupt the neuron-astrocyte coupling, while activated microglia release pro-inflammatory cytokines (TNF-α, IL-6) to amplify neurotoxicity. Collectively, these metabolic derangements drive glutamate/D-serine dysregulation, neuronal dysfunction, and PD pathogenesis. Created with Adobe Illustrator 2020.

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  Figure 4. Fatty acid-dependent polarization of microglia in the central nervous system. Resting (M0) microglia maintain homeostasis and survey the CNS microenvironment. In response to saturated fatty acids (SFAs, e.g., palmitic acid) or LPS, microglia undergo pro-inflammatory (M1) polarization via TLR4-mediated activation of NF-κB and MAPK signaling. This drives amoeboid morphology, iNOS upregulation, ROS generation, and pro-inflammatory cytokine release (TNF-α, IL-1β, IL-6), leading to neurotoxicity. Conversely, polyunsaturated fatty acids (PUFAs, e.g., DHA/EPA) promote anti-inflammatory (M2) polarization through GPR120/PPARγ signaling. This activates pathways including AMPK, PI3K/Akt, and Nrf2, inhibits NF-κB, and induces hyper-ramified morphology, Arg-1/CD206 expression, anti-inflammatory cytokine release (IL-10, TGF-β), and enhanced debris phagocytosis, supporting neuroprotection. Created with Adobe Illustrator 2020.

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  Figure 5. α-synuclein fibril formation and interaction between α-synuclein and fatty acids in the pathogenesis of PD. Under specific conditions, the natively unstructured monomer can convert into oligomers, which can further aggregate into protofibrils and finally into highly ordered cross-β-sheet fibrils (left panel). α-synuclein and fatty acids mutually interact and influence each other, contributing to disease onset and progression (right panel). Created with FigDraw 2.0 (Copyright Code: UTITR40aaf).