Lipid metabolism dysregulation in Parkinson’s disease: Mechanistic insights and therapeutic implications

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective degeneration of nigrostriatal dopaminergic neurons and pathological accumulation of α-synuclein (α-Syn) aggregates. Emerging evidence indicates the important role of lipid metabolism dysregulation in driving these pathological features. As major structural components of brain tissue and critical regulators of neuronal function, lipids are involved in diverse biological processes, including cell membrane formation, intercellular signaling, energy storage, and homeostasis. Their dysregulation directly affects neural functions, such as synaptic transmission, antioxidant defense, and inflammatory modulation. PD is recognized not only as a “proteinopathy” but also as an “organelle communication disorder,” involving dysfunction of membrane contact sites across mitochondria, endoplasmic reticulum, lysosomes, and lipid droplets (LDs)—a process that may constitute an early pathogenic event. It is noteworthy that several proteins mediating LDs-organelle contacts are disease-related factors encoded by mutated genes in inherited neurological and metabolic disorders. Despite the extensive communication between intracellular LDs and other organelles through these contact sites, the systematic integration of lipid metabolism dysregulation into core PD pathogenesis remains elusive. This review provides a comprehensive overview of the mechanisms underlying lipid-organelle interactions in PD pathogenesis, with a specific focus on the triangular interplay among the three core pathological hallmarks: α-Syn aggregation, mitochondrial dysfunction, and neuroinflammation, and their convergence with the lipid metabolic network. By analyzing molecular mechanisms and clinical implications, with particular focus on lipid-related biomarkers and therapeutic strategies targeting organelle communication pathways, this review aims to provide new insights into the role of lipid dyshomeostasis in PD pathogenesis and identify feasible therapeutic targets.

Graphical abstract

Keywords

Parkinson’s disease / Lipid metabolism / Organelle communication / α-Synuclein / Mitochondrial dysfunction

Funding

This work was funded by the Natural Science Foundation of China (82571429 to Y.X., 82221001 to S.W.), the Natural Science Basic Research Program of Shaanxi (2024JC-YBQN-0774 to Y.X.), and the Open Fund of Key Laboratory of Clinical Neurology, Ministry of Education (2025A02 to Y.X.).

Conflict of interest

Sheng-Xi Wu is an Associate Editor of this journal but was not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. Separately, other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.

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