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In vivo demonstration that α-synuclein oligomers are toxic

Beate Winner, Roberto Jappelli, Samir K. Maji, Paula Desplats, Leah Boyer, Stefan Aigner, Claudia Hetzer, Thomas Loher, Marçal Vilar, Silvia Campioni,

Proceedings of the National Academy of Sciences · 2011 · 1.5K citations · 30 references

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TL;DR

Protein aggregation into oligomers and amyloid fibrils, including α‑synuclein in Parkinson’s disease, is considered a disease‑causing toxic mechanism. The study aimed to generate α‑synuclein mutants favoring oligomer or fibril formation and assess their neurotoxicity in a rat lentivirus model of dopaminergic neuron loss. Mutants were expressed in rats using a lentiviral vector, and dopaminergic neuron loss in the substantia nigra was quantified. Oligomer‑forming α‑syn variants (E57K, E35K) caused the greatest substantia nigra dopaminergic loss, whereas rapidly fibril‑forming variants were less toxic, confirming that α‑syn oligomers are in vivo neurotoxic and may disrupt membranes.

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.