Lipid Alterations and Pathogenic Roles in Synucleinopathies

Mounting evidence highlights a role for lipid alterations and defects in lipid signaling in age-related neurodegenerative diseases such as Parkinson's disease (PD) and related conditions (collectively referred to as synucleinopathies). This growing interest is driven by several key findings: (1) lipid membranes are components of Lewy bodies and Lewy neurites, which are prototypical proteinaceous intraneuronal inclusions of PD and other synucleinopathies, primarily composed of α-synuclein (αS); (2) αS shares structural similarities with lipid-binding proteins and has been reported to bind to lipids; (3) glucocerebrosidase, a key enzyme in sphingolipid metabolism, is a major PD risk factor; (4) other enzymes involved in glycolipid and phospholipid regulation, such as diacylglycerol kinase-θ and fatty acid elongase-7, also contribute to PD risk; (5) αS alterations impact lipid homeostasis; (6) αS transiently binds lipid membranes, affecting its conformation. Given these findings, we review what is known about the role of lipids in normal αS biology as well as in the pathogenesis of PD and related conditions. We also highlight areas where further research is warranted.