Parkinson's disease: proteinopathy or lipidopathy?

Lipids play a more significant role in Parkinson's disease and its related brain disorders than is currently recognized, supporting a lipid cascade. The 14 kDa protein alpha-synuclein (alpha S) is strongly associated with Parkinson's disease (PD), dementia with Lewy bodies (DLB), other synucleinopathies such as multiple system atrophy, and even certain forms of Alzheimer's disease. Rigorously deciphering the biochemistry of alpha S in native systems is the key to developing treatments. alpha S is highly expressed in the brain, the second most lipid-rich organ, and has been proposed to be a lipid-binding protein that physiologically interacts with phospholipids and fatty acids (FAs). alpha S-rich cytoplasmic inclusions called Lewy bodies and Lewy neurites are the hallmark lesions of synucleinopathies. Excess alpha S-membrane interactions may trigger proteinaceous alpha S aggregation by stimulating its primary nucleation. However, alpha S may also exert its toxicity prior to or independent of its self-aggregation, e.g., via excessive membrane interactions, which may be promoted by certain lipids and FAs. A complex alpha S-lipid landscape exists, which comprises both physiological and pathological states of alpha S. As novel insights about the composition of Lewy lesions occur, new lipid-related PD drug candidates emerge, and genome-wide association studies (GWAS) increasingly validate new hits in lipid-associated pathways, it seems timely to review our current knowledge of lipids in PD and consider the roles for these pathways in synucleinopathies.alpha S <-> lipid interplay: aspects of cellular alpha S homeostasis (blue oval), aspects of lipid homeostasis (green oval), and overlapping aspects. Pathological states are labeled in red. Simplified schematic of both select alpha S and select lipid species. Several existing publications suggest alpha S effects on lipids and vice versa, as indicated by arrows. DG diglyceride, ER endoplasmic reticulum, FA fatty acid, LD, lipid droplet, TG triglyceride.