α-Synuclein (α-Syn) is a neuronal protein that accumulates progressively in Parkinson's disease (PD) and related synucleinopathies. Attempting to identify cellular factors that affect α-Syn neuropathology, we previously reported that polyunsaturated fatty acids (PUFAs) promote α-Syn oligomerization and aggregation in cultured cells. We now report that docosahexaenoic acid (DHA), a 22:6 PUFA, affects α-Syn oligomerization by activating retinoic X receptor (RXR) and peroxisome proliferator-activated receptor γ2 (PPARγ2). In addition, we show that dietary changes in brain DHA levels affect α-Syn cytopathology in mice transgenic for the PD-causing A53T mutation in human α-Syn. A diet enriched in DHA, an activating ligand of RXR, increased the accumulation of soluble and insoluble neuronal α-Syn, neuritic injury and astrocytosis. Conversely, abnormal accumulations of α-Syn and its deleterious effects were significantly attenuated by low dietary DHA levels. Our results suggest a role for activated RXR/PPARγ 2, obtained by elevated brain PUFA levels, in α-Syn neuropathology.