Changes in the cellular fatty acid profile drive the proteasomal degradation of α-synuclein and enhance neuronal survival

Mary Xylaki, Ioanna Boumpoureka, Maroula G. Kokotou, Theodoros Marras, Georgia Papadimitriou, Ismini Kloukina, Victoria Magrioti, George Kokotos, Kostas Vekrellis, Evangelia Emmanouilidou*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

7 Citations (Scopus)


Parkinson's disease is biochemically characterized by the deposition of aberrant aggregated α-synuclein in the affected neurons. The aggregation properties of α-synuclein greatly depend on its affinity to bind cellular membranes via a dynamic interaction with specific lipid moieties. In particular, α-synuclein can interact with arachidonic acid (AA), a polyunsaturated fatty acid, in a manner that promotes the formation of α-helix enriched assemblies. In a cellular context, AA is released from membrane phospholipids by phospholipase A2 (PLA2). To investigate the impact of PLA2 activity on α-synuclein aggregation, we have applied selective PLA2 inhibitors to a SH-SY5Y cellular model where the expression of human wild-type α-synuclein is correlated with a gradual accumulation of soluble oligomers and subsequent cell death. We have found that pharmacological and genetic inhibition of GIVA cPLA2 resulted in a dramatic decrease of intracellular oligomeric and monomeric α-synuclein significantly promoting cell survival. Our data suggest that alterations in the levels of free fatty acids, and especially AA and adrenic acid, promote the formation of α-synuclein conformers which are more susceptible to proteasomal degradation. This mechanism is active only in living cells and is generic since it does not depend on the absolute quantity of α-synuclein, the presence of disease-linked point mutations, the expression system or the type of cells. Our findings indicate that the α-synuclein-fatty acid interaction can be a critical determinant of the conformation and fate of α-synuclein in the cell interior and, as such, cPLA2 inhibitors could serve to alleviate the intracellular, potentially pathological, α-synuclein burden.

Original languageEnglish
Pages (from-to)15123-15145
Number of pages23
JournalFASEB Journal
Issue number11
Publication statusPublished - 1 Nov 2020
Externally publishedYes


  • alpha-synuclein
  • arachidonic acid
  • degradation
  • oligomers
  • Parkinson's disease
  • phospholipase A
  • proteasome


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