Objective: To find new potential druggable targets that prevent alpha-synuclein aggregation and toxicity in Parkinson’s disease.

Background: Alpha-synuclein (aS) is the primary protein deposited in Parkinson’s disease (PD). Oligomeric intermediates of aS on the aggregation pathway are associated with neurotoxicity in PD. Preventing aS aggregation may slow down or reverse PD progression, but no therapeutic approach to remove toxic aS species or prevent their formation exists today.

Methods: We performed a proteome-wide, 14,000 protein functional screen to identify new proteins that can inhibit aS aggregation into oligomers and amyloid fibrils. We probed the impact of target proteins on aS fibril formation in vitro by thioflavin T fluorescence and probed toxicity in a mutant aS yeast model and in neuronal model cells (SH-EP) and primary neurons.

Results: Our screen identified 13 new proteins that inhibited aS aggregation in an ATP-independent process. Ezrin, a microtubule-associated protein that modulates neuronal motility, was the most potent of these inhibitors, preventing aS aggregation at molar ratios of 1:100 and below. Ezrin prevents aS aggregation and toxicity in a yeast model and rescues aS toxicity in neurons. Surprisingly, aS aggregated more rapidly in the presence of Ezrin but didn’t form amyloid fibrils.

Conclusions: Ezrin acts as a new and potent unconventional chaperone that forces early aS amyloid intermediates into off-pathway aggregates, and thus eliminates them from the amyloid pathway and prevents primary nucleation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/unconventional-chaperone-inhibits-alpha-synuclein-amyloid-formation-by-promoting-off-pathway-aggregation/