a-Synuclein Neuropathology is Controlled by Nuclear Hormone Receptors and Enhanced by Docosahexaenoic Acid in A Mouse Model for Parkinson's Disease

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