Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity
Villar-Piqué A., Lopes da Fonseca T., Sant’Anna R., Szegö ÉM., Fonseca-Ornelas L., Pinho R., Carija A., Gerhardt E., Masaracchia C., Abad Gonzalez E., Rossetti G., Carloni P., Fernández CO., Foguel D., Milosevic I., Zweckstetter M., Ventura S., Outeiro TF.
Significance Many neurodegenerative diseases are characterized by the abnormal accumulation of aggregated proteins in the brain. In Parkinson’s disease and related disorders, this process involves the accumulation of α-synuclein (aSyn). Thus, understanding the relationship between aSyn aggregation and pathological conditions is essential for the development of novel and efficient therapies against these disorders. Here, we studied the effects that different aSyn species have on neurons using a combination of neurodegeneration-associated factors: the H50Q aSyn mutant and the presence of copper. Importantly, we demonstrate that exogenous aSyn promotes toxicity and inclusion formation, and that these effects are inversely correlated. Our data shed light onto the pathological mechanisms associated with aSyn aggregation, forming the foundation for future therapeutic strategies.