In vivo demonstration that {alpha}-synuclein oligomers are toxic.

Proc Natl Acad Sci U S A
Publication Year: 
B Winner , R Jappelli , S K Maji , P A Desplats , L Boyer , S Aigner , C Hetzer , T Loher , M Vilar , S Campioni , C Tzitzilonis , A Soragni , S Jessberger , H Mira , A Consiglio , E Pham , E Masliah , F H Gage , R Riek
Public Summary: 
Scientific Abstract: 
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 alpha-synuclein (alpha-syn) from monomers, via oligomeric intermediates, into amyloid fibrils is considered the disease-causative toxic mechanism. We developed alpha-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 alpha-syn variants that form oligomers (i.e., E57K and E35K), whereas the alpha-syn variants that form fibrils very quickly are less toxic. We show that alpha-syn oligomers are toxic in vivo and that alpha-syn oligomers might interact with and potentially disrupt membranes.

© 2013 California Institute for Regenerative Medicine