Parkinson disease is a fatty acidopathy

On the basis of extensive mechanistic research over three decades, Parkinson disease (PD) and related synucleinopathies have been proposed to be combined proteinopathies and lipidopathies. Evidence strongly supports a physiological and pathogenic interplay between the disease-associated protein α-synuclein and lipids, with a demonstrable role for lipids in modulating PD phenotypes in the brain. Here, we refine this hypothesis by proposing PD to be a disease specifically involving metabolic dysregulation of fatty acids, a 'fatty acidopathy'. We review extensive findings from many laboratories supporting the perspective that PD centres on fatty acid dyshomeostasis - alterations in the fatty acid-ome - as the critical feature of lipid aberration in PD and other α-synucleinopathies. This construct places transient α-synuclein binding to fatty acid side chains of cytoplasmic vesicles as a principal contributor to the biology of PD-relevant α-synuclein-membrane interactions. We propose that α-synuclein-fatty acid interactions in the fatty acid-rich brain are interdependent determinants of the gradual progression from neuronal health to PD, with attendant therapeutic implications.