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.