Changes in the cellular fatty acid profile drive the proteasomal degradation of α-synuclein and enhance neuronal survival.
FASEB JOURNAL(2020)
Abstract
Parkinson's disease is biochemically characterized by the deposition of aberrant aggregated alpha-synuclein in the affected neurons. The aggregation properties of alpha-synuclein greatly depend on its affinity to bind cellular membranes via a dynamic interaction with specific lipid moieties. In particular, alpha-synuclein can interact with arachidonic acid (AA), a polyunsaturated fatty acid, in a manner that promotes the formation of alpha-helix enriched assemblies. In a cellular context, AA is released from membrane phospholipids by phospholipase A(2)(PLA(2)). To investigate the impact of PLA(2)activity on alpha-synuclein aggregation, we have applied selective PLA(2)inhibitors to a SH-SY5Y cellular model where the expression of human wild-type alpha-synuclein is correlated with a gradual accumulation of soluble oligomers and subsequent cell death. We have found that pharmacological and genetic inhibition of GIVA cPLA(2)resulted in a dramatic decrease of intracellular oligomeric and monomeric alpha-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 alpha-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 alpha-synuclein, the presence of disease-linked point mutations, the expression system or the type of cells. Our findings indicate that the alpha-synuclein-fatty acid interaction can be a critical determinant of the conformation and fate of alpha-synuclein in the cell interior and, as such, cPLA(2)inhibitors could serve to alleviate the intracellular, potentially pathological, alpha-synuclein burden.
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Key words
alpha-synuclein,arachidonic acid,degradation,oligomers,Parkinson's disease,phospholipase A(2),proteasome
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