Work

Subtypes of Fatty Acidopathy in Parkinson’s Disease: A Mechanistic and Precision Medicine Perspective

Year: 2026

Type: article

Abstract: The conceptual evolution of Parkinson’s disease (PD) from a protein-centric disorder to a metabolic disease has gained substantial momentum. While the lipidopathy framework encompasses dysregulation across all lipid classes, the emerging fatty acidopathy concept offers a mechanistically tractable refinement, focusing on fatty acid side-chain dyshomeostasis as a critical determinant of α-synuclein conformation and aggregation. This short review argues that fatty acidopathy is a mechanistically defined, conditionally applicable subset within the broader lipidopathy framework, with relevance that varies across PD subtypes. We examine the hierarchical relationship between these concepts, the evidence supporting fatty acidopathy in α-synuclein-driven PD, and the therapeutic implications of targeting upstream metabolic dysregulation. We critically discuss the translational challenges of current lipidomic approaches, including distinguishing disease-specific from state-specific metabolic signals, defining pathological trigger points, and validating biomarkers across diverse populations. We acknowledge that current evidence remains largely associative and that rigorous, stratified trial designs are required to bridge the preclinical-to-clinical gap. The fatty acidopathy framework offers a conceptual foundation for future subtype-specific therapeutic development in PD.

Source: Cellular and Molecular Neurobiology

DOI: 10.1007/s10571-026-01813-8

Authors: Duan Lu Hou, Yun-Cheng Wu, Eng King Tan, Zhi Dong Zhou