title: Α-synuclein neuropathology is controlled by nuclear hormone receptors and enhanced by docosahexaenoic acid in a mouse model for Parkinson's disease.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Yakunin
authors.forename: Virginie
authors.initials: V
authors.lastname: Loeb
authors.forename: Haya
authors.initials: H
authors.lastname: Kisos
authors.forename: Yoav
authors.initials: Y
authors.lastname: Biala
authors.forename: Shlomo
authors.initials: S
authors.lastname: Yehuda
authors.forename: Yoel
authors.initials: Y
authors.lastname: Yaari
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Selkoe
authors.forename: Ronit
authors.initials: R
authors.lastname: Sharon
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D051844:alpha-Synuclein; D004281:Docosahexaenoic Acids