α-Synuclein neuropathology is controlled by nuclear hormone receptors and enhanced by docosahexaenoic acid in a mouse model for Parkinson's disease

Eugenia Yakunin, Virginie Loeb, Haya Kisos, Yoav Biala, Shlomo Yehuda, Yoel Yaari, Dennis J. Selkoe, Ronit Sharon

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

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.

Original languageEnglish
Pages (from-to)280-294
Number of pages15
JournalBrain Pathology
Volume22
Issue number3
DOIs
StatePublished - May 2012
Externally publishedYes

Keywords

  • Alpha synuclein
  • Docosahexaenoic acid
  • Parkinson's disease
  • Peroxisome proliferator-activated receptors (PPAR)γ
  • Protein oligomerization and aggregation
  • Retinoic X receptor (RXR)

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