Uncovering the Complexity of Synucleinopathies: An Ongoing Tale Between Proteins and Lipids

Neurodegenerative diseases are pathological states characterized by progressive alterations in brain homeostasis during aging. Synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are defined neuropathologically by the accumulation of inclusions known as Lewy bodies and Lewy neurites. These structures have complex compositions that, in addition to α-synuclein (aSyn), encompass a lipid core and nucleic acids, suggesting that proteostasis imbalances alone may not fully explain the origin of the pathognomonic inclusions. Recent research is uncovering the role of lipids in early disease stages. Imbalances in lipidostasis may arise as a consequence of lifestyle behaviors, impaired function or expression of central metabolic enzymes, or most likely, from a combination of both. Multiple experimental approaches and models have been used to investigate the underlying mechanisms associated with changes in both lipid-related enzymes and lipid species profiles seen in patients with synucleinopathies. However, our understanding of such mechanisms is still incomplete, especially in the context of humans, where mechanistic studies are not possible. Therefore, in this review, we highlight the latest research on aSyn-lipid interaction across different experimental models and propose that early disruptions in neuronal lipid metabolism can lead to altered membrane composition, contributing to the aggregation and accumulation of aSyn. Ultimately, we posit that elucidating the role of lipids in synucleinopathies may enable not only further patient classification but also the development of personalized treatment approaches. © 2025 International Parkinson and Movement Disorder Society.