Changes in the cellular fatty acid profile drive the proteasomal degradation of α‐synuclein and enhance neuronal survival. Issue 11 (15th September 2020)

• Record Type: Journal Article
• Authors: Xylaki, Mary; Boumpoureka, Ioanna; Kokotou, Maroula G.; Marras, Theodoros; Papadimitriou, Georgia; Kloukina, Ismini; Magrioti, Victoria; Kokotos, George; Vekrellis, Kostas; Emmanouilidou, Evangelia
• Is Part Of: FASEB journal. Volume 34:Issue 11(2020)
• Page Start: 15123
• Page End: 15145
• Publication Date: 2020-09-15
• Subjects: alpha‐synuclein -- arachidonic acid -- degradation -- oligomers -- Parkinson's disease -- phospholipase A2 -- proteasome; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.202001344R
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract: 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.