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In vivo demonstration that α-synuclein oligomers are toxic

2011; National Academy of Sciences; Volume: 108; Issue: 10 Linguagem: Inglês

10.1073/pnas.1100976108

1091-6490

Beate Winner, Roberto Jappelli, Samir K. Maji, Paula Desplats, Leah Boyer, Stefan Aigner, Claudia Hetzer, Thomas Loher, Marçal Vilar, Silvia Campioni, Christos Tzitzilonis, Alice Soragni, Sebastian Jessberger, Helena Mira, Antonella Consiglio, Emiley Pham, Eliezer Masliah, Fred H. Gage, Roland Riek,

Neurological diseases and metabolism

The aggregation of proteins into oligomers and amyloid fibrils is characteristic of several neurodegenerative diseases, including Parkinson disease (PD). In PD, the process of aggregation of α-synuclein (α-syn) from monomers, via oligomeric intermediates, into amyloid fibrils is considered the disease-causative toxic mechanism. We developed α-syn mutants that promote oligomer or fibril formation and tested the toxicity of these mutants by using a rat lentivirus system to investigate loss of dopaminergic neurons in the substantia nigra. The most severe dopaminergic loss in the substantia nigra is observed in animals with the α-syn variants that form oligomers (i.e., E57K and E35K), whereas the α-syn variants that form fibrils very quickly are less toxic. We show that α-syn oligomers are toxic in vivo and that α-syn oligomers might interact with and potentially disrupt membranes.