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Advanced Neurology Lipid metabolism and Parkinson’s disease

synthesis and vulnerable to pathological disruption. In and valerate levels. 76,77 This distributional imbalance
addition, regional metabolic heterogeneity exists—e.g., the enables gut-derived SCFAs to indirectly exacerbate
midbrain, cerebellum, and olfactory bulb show higher FA CNS pathology by abnormally activating microglia,
synthesis rates than the hippocampus and cortex, with a promoting α-Syn misfolding, and impairing protein
bias toward ω-3/ω-6 PUFAs (e.g., DHA and arachidonic degradation systems. Specifically, butyrate acts as a histone
acid [AA]) compared to the synthesis of MUFAs in deacetylase (HDAC) inhibitor. Insufficient butyrate levels
peripheral tissues. This compartmentalized synthesis inhibit HDAC-dependent autophagy gene expression
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profile is essential for neuronal function and synaptic and impair ubiquitin-proteasome system function,
plasticity; its disruption directly contributes to PD-related ultimately leading to misfolded protein accumulation,
neuronal dysfunction. mitochondrial dysfunction, and neuroinflammatory
De novo FA synthesis in mammals involves acetyl-CoA responses. 71,78-83 These findings highlight SCFAs’ dual roles
carboxylase and FA synthase (FASN), converting acetyl- in CNS pathophysiology, which are concentration- and
CoA to PA; this product is subsequently modified by distribution-dependent—i.e., exerting neuroprotective
stearoyl-CoA desaturase 1 (SCD1) and elongases to form or neurotoxic effects based on their compartmental
MUFAs and PUFAs. 59,60 Studies indicate that the abnormal distribution and metabolic context, thereby linking gut
accumulation of PUFAs and cholesterol lipids promotes dysbiosis to PD pathogenesis and offering potential targets
α-Syn misfolding and aggregation, while aberrant binding for dietary or probiotic intervention.
of α-Syn to oxidized lipid metabolites damages key 3.2. Phospholipid remodeling: From mitochondrial
organelles such as mitochondria. 61,62 Notably, PUFAs are failure to α-Syn aggregation
significantly reduced in the SNc of PD patients—particularly
the members of the ω-3 PUFA families (such as DHA) and 3.2.1. CL
the ω-6 PUFA families (such as AA). As PUFAs, especially CL, a unique diphosphatidylglycerol enriched in the
AA, are major substrates for lipid peroxidation, their inner mitochondrial membrane, maintains membrane
depletion reduces membrane fluidity and the production ultrastructure, respiratory chain assembly, mitochondrial
of neuroprotective mediators. 63-65 Notably, decreased dynamics, and mitophagy. Its biosynthesis involves
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PUFAs may reflect or exacerbate the severe oxidative stress phosphatidylglycerol conversion to immature CL
state in PD. 59,66 Furthermore, FA metabolic dysregulation through CL synthase (CRLS1), followed by remodeling
impairs the activity and efficiency of FA oxidation (e.g., tafazzin-mediated replacement of FA chains with
enzymes. Oxidative stress products (e.g., 4-HNE) directly unsaturated species such as linoleic acid) to form mature
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damage neurons and accelerate α-Syn oligomerization CL. Dysregulation of CL metabolism, characterized
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and fibrillization. Concurrently, reduced early CPT1 by alterations in its content, structure, and distribution,
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activity observed in PD patients causes the accumulation impairs mitochondrial function. These abnormalities
of long-chain acyl cofactors (e.g., acylcarnitine [16:0] lead to pathological processes such as oxidative stress and
and acylcarnitine [16:1]), which inhibits mitochondrial apoptosis, which are implicated in various disease states,
respiratory chain complexes, reduces ATP production, and particularly PD. Abnormal CL metabolism fragments
disrupts neuronal energy metabolism. 69 mitochondrial cristae, disrupts respiratory chain complex
Short-chain FAs (SCFAs) are saturated aliphatic organic I/III assembly, reduces electron transfer efficiency, and
acids with 1–6 carbon atoms, primarily comprising 60% triggers ROS bursts—a key source of oxidative stress
85,86
acetate (two carbon atoms, C2), 20% propionate (three in PD. CL translocates ectopically to the outer
carbon atoms, C3), and 20% butyrate (four carbon atoms, mitochondrial membrane, serving as a molecular platform
C4). 70-72 As key gut–brain axis regulators, SCFAs modulate for BCL2-associated X (BAX) protein oligomerization and
87,88
CNS function through multiple pathways: their deficiency MOMP, driving apoptosis in dopaminergic neurons.
disrupts intestinal metabolic homeostasis, facilitating Physiologically, CL binds the N-terminal domain of
α-Syn misfolding and prion-like propagation. 73-78 PD α-Syn through electrostatic interactions, maintaining
patients exhibit gut dysbiosis—reduced abundance of its α-helical conformation and preventing misfolding.
SCFA-producing genera (e.g., Roseburia and Prevotella)— In PD, decreased CL content or oxidative damage (e.g.,
causes an approximately 30% decrease in total fecal SCFAs, complex II-derived ROS attacking CL dienophile bonds)
predominantly affecting acetate, propionate, and butyric causes α-Syn dissociation, promoting β-sheet-rich toxic
acids. 74,76 Conversely, intestinal mucosal barrier disruption oligomers and Lewy body formation. 18,86 Recent studies
leads to abnormal SCFA leakage into the bloodstream, show that the SNc from PD patients exhibits reduced total
significantly elevating plasma propionate, butyrate, CL content and decreased levels of unsaturated FAs; these

Volume 4 Issue 4 (2025) 35 doi: 10.36922/AN025320086