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- W2468270902 abstract "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. We performed a proteome-wide, 14,000 protein functional screen to identify new proteins that can inhibit aS aggregation into oligomers and amyloid fibrils. The 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.Our preliminary data demonstrate that Ezrin prevents aS aggregation and toxicity in a yeast model and rescues aS toxicity in neuronal model cells (SH-EP) and primary neurons. Surprisingly, aS aggregated more rapidly in the presence of Ezrin but didn’t form amyloid fibrils. The protein forces early aS aggregation intermediates into off-pathway aggregates, and thus eliminates them from the amyloid pathway and prevents primary nucleation.Unlike the in formation of amyloid fibrils, it was not the hydrophobic NAC region of aS that initiated aggregation in the presence of Ezrin, but rather the highly charged N-terminus. Based on these data, we conclude that Ezrin initiates off-pathway aggregation by a process that is driven by complementary charge interaction rather than by hydrophobic forces and which may be analogous to complex coacervation." @default.
- W2468270902 created "2016-07-22" @default.
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- W2468270902 date "2016-02-01" @default.
- W2468270902 modified "2023-09-28" @default.
- W2468270902 title "Unconventional Chaperone Inhibits Amyloid Formation by Promoting off-Pathway Aggregation" @default.
- W2468270902 doi "https://doi.org/10.1016/j.bpj.2015.11.2950" @default.
- W2468270902 hasPublicationYear "2016" @default.
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