Parkinson’s Disease (PD) affects over 10 million people worldwide. It is an irreversible, neurodegenerative condition with no cure. Patients with PD have impaired motor functions like tremors, stiffness, slow movement, and poor balance. It is influenced by a complex interplay of genetics, environmental factors, or both. PD is characterized by the lack of dopamine and the presence of Lewy Bodies, which are clumps of α-Syn, in the brain. Recent advances in lipidomics, which is the comprehensive study of the set of lipids in a biological system, have provided valuable insights into the role of lipid metabolism and PD progression.
Lipids are major components of the central nervous system, playing both structural and functional roles. A team of researchers from Soochow University in Suzhou, Jiangsu, China, conducted a comprehensive review to understand the association between lipid metabolism disruptions and PD pathogenesis. Their study, which was led by Professor Chunfeng Liu, was made available online on May 26, 2025 and published in Volume 138, Issue 12 of Chinese Medical Journal on June 20, 2025 . “ This review explores the roles of various lipid classes and lipoproteins in PD, examining how lipid disruptions contribute to α-Syn aggregation, mitochondrial dysfunction, and neuroinflammation,” explains Prof. Zhao.
Lipids are vital in preserving brain homeostasis. “ In the healthy brain, astrocytes convert circulating fatty acids (FAs) into lipid droplets (LDs), which are distributed to neurons, oligodendrocytes, and microglia to maintain metabolic balance,” explains Prof. Zhao . Astrocytes maintain the integrity of the Blood Brain Barrier (BBB), which is rich in cholesterol and sphingolipids. Disruption in lipid metabolism compromises the integrity of the BBB, allowing invasion of toxic components to enter the brain, ultimately contributing to neurodegeneration. Dysregulation of lipid metabolism in microglia cells impacts iron-dependent lipid peroxidation, oxidative damage, and inflammation. Myelin formation is an important function of oligodendrocytes. Mutations in the gene GBA1 , as seen in PD, downregulate myelin formation, leading to α-Syn aggregation and neurodegeneration.
Impaired metabolism of various lipid classes, including fatty acids [monounsaturated (MUFA), and polyunsaturated (PUFA)], sphingolipids (such as ceramide and sphingosine), glycerophospholipids (including monoacylglycerol, diacylglycerol, triacylglycerol, and CDP-diacylglycerol), as well as cholesterol and lipoproteins (LDL, HDL, and VLDL), has been shown to contribute significantly to the progression of neurodegenerative diseases.
Understanding the underlying genetic factors and signalling mechanisms is crucial for developing therapies for PD. Mutations in genes that regulate lipid metabolism in the brain can increase disease risk. One such example is GBA1 , the most common genetic risk factor for PD. Mutations in the GBA1 can lead to lysosomal dysfunction, α-Syn aggregation, and mitochondrial impairment. Other PD-associated genes, such as PLA2G6, VPS13/VPS35 , LRRK2 , and ACSL4 alter lipid metabolism, leading to disease progression. Iron accumulation leads to lipid peroxidation and ferroptosis (iron-dependent cell death), which is a classic manifestation in PD patients. “ Altered lipid metabolism in PD disrupts α-Syn, impairing mitochondrial function, autophagy, and inflammation and leading to cellular dysfunction ,” says Prof. Zhao while highlighting the driving mechanisms behind PD progression.
Considering the critical role of lipids in maintaining brain homeostasis, they represent a promising therapeutic target for PD. Lipid-lowering modifiers (LLMs) work by attenuating inflammation and oxidative stress. Statins such as simvastatin, lovastatin, and atorvastatin exert neuroprotective effects by reducing inflammation and improving motor function. Dietary supplementation with niacin (vitamin B3), vitamin D, and fish oil (rich in omega-3 fatty acids) also stalls the progression of PD. Dysbiosis within the gut can worsen the progression of PD. Therefore, including Short-chain FAs (SCFAs), such as a butyrate-rich diet, can protect against neuroinflammation. “Priorities for future research include elucidating the causal role of lipid changes in PD, developing BBB-penetrating delivery systems, and designing personalized treatment strategies based on genetic and metabolic profiles. Advancing our understanding of lipid biology in PD will likely lead to more targeted and effective therapeutic interventions,” concludes Prof. Zhao.
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Reference
DOI: http://doi.org/10.1097/CM9.0000000000003627
Chinese Medical Journal
Systematic review
Not applicable
Lipid metabolism in health and disease: Mechanistic and therapeutic insights for Parkinson’s disease
20-Jun-2025
The authors declare no competing interests