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
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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.