Alpha-synuclein aggregation and toxicity: structural biology meets cell biology

DELGADO OCAÑA, SUSANA; GONZALEZ, NAZARENO; GENTILE, IÑAKI; GARRO, HUGO A.; SCHIBICH, DANIELA; MARIA E. CHESTA; MENACHO MÁRQUEZ, MAURICIO; FERNÁNDEZ, CLAUDIO O.

Córdoba

Congreso; XXXIII CONGRESO ANUAL SAN 2018; 2018

Sociedad Argentina de Investigación en Neurociencias

Amyloid aggregation of alpha-synuclein (αS) in Parkinson?s disease (PD) results in cellular toxicityand neuronal death. Several mutations in αS gene are associated with familial PD, supporting acentral role for the protein in the development of the disease. However, the precise contributionof αS aggregates to neuronal impairment and death is not well understood. Previous work in ourlab demonstrated that aromatic side chains of the N-terminal tyrosine residue at position 39 (Y39)of αS plays a critical role in its fibrillation pathway. In order to understand the key role of Y39residue on αS aggregation and toxicity, we designed different point mutants of the protein.Through the combination of biophysics and cell-based assays, we demonstrated that replacementof Tyr by Ala or Leu at position 39 led to protein variants with different amyloidogenic potential.Interestingly, strong correlation was observed between the in vitro and in cell studies. Altogether,our data highlight the importance of combining structural and cell biology strategies, and opennew perspectives to elucidate the molecular basis behind the amyloid aggregation of the proteinαS.