title: In vivo demonstration that alpha-synuclein oligomers are toxic.
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 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.
authors.affiliation: Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Beate
authors.initials: B
authors.lastname: Winner
authors.forename: Roberto
authors.initials: R
authors.lastname: Jappelli
authors.forename: Samir K
authors.initials: SK
authors.lastname: Maji
authors.forename: Paula A
authors.initials: PA
authors.lastname: Desplats
authors.forename: Leah
authors.initials: L
authors.lastname: Boyer
authors.forename: Stefan
authors.initials: S
authors.lastname: Aigner
authors.forename: Claudia
authors.initials: C
authors.lastname: Hetzer
authors.forename: Thomas
authors.initials: T
authors.lastname: Loher
authors.forename: Marçal
authors.initials: M
authors.lastname: Vilar
authors.forename: Silvia
authors.initials: S
authors.lastname: Campioni
authors.forename: Christos
authors.initials: C
authors.lastname: Tzitzilonis
authors.forename: Alice
authors.initials: A
authors.lastname: Soragni
authors.forename: Sebastian
authors.initials: S
authors.lastname: Jessberger
authors.forename: Helena
authors.initials: H
authors.lastname: Mira
authors.forename: Antonella
authors.initials: A
authors.lastname: Consiglio
authors.forename: Emiley
authors.initials: E
authors.lastname: Pham
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Fred H
authors.initials: FH
authors.lastname: Gage
authors.forename: Roland
authors.initials: R
authors.lastname: Riek
mesh_terms: D000818:Animals; D001704:Biopolymers / Q000633:toxicity*; D001921:Brain / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D051381:Rats; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*
chemical_list: D001704:Biopolymers; D051844:alpha-Synuclein