Changes in the cellular fatty acid profile drive the proteasomal degradation of α-synuclein and enhance neuronal survival.
FASEB J
; 34(11): 15123-15145, 2020 11.
Article
en En
| MEDLINE
| ID: mdl-32931072
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Ácido Araquidónico
/
Alfa-Sinucleína
/
Fosfolipasas A2
/
Ácidos Grasos
/
Ácidos Grasos Insaturados
/
Inhibidores de Fosfolipasa A2
/
Neuronas
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
FASEB J
Asunto de la revista:
BIOLOGIA
/
FISIOLOGIA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Grecia