Abstract
α-Synuclein (aSyn) aggregation is an attractive target for therapeutic development for a range of neurodegenerative conditions, collectively termed synucleinopathies. Here, we probe the mechanism of action of a peptide 4554W, (KDGIVNGVKA), previously identified through intracellular library screening, to prevent aSyn aggregation and associated toxicity. We utilize NMR to probe association and identify that 4554W associates with a “partially aggregated” form of aSyn, with enhanced association occurring over time. We also report the ability of 4554W to undergo modification through deamidation of the central asparagine residue, occurring on the same timescale as aSyn aggregation in vitro, with peptide modification enhancing its association with aSyn. Additionally, we report that 4554W can act to reduce fibril formation of five Parkinson’s disease associated aSyn mutants. Inhibitory peptide binding to partially aggregated forms of aSyn, as identified here, is particularly attractive from a therapeutic perspective, as it would eliminate the need to administer the therapy at pre-aggregation stages, which are difficult to diagnose. Taken together the data suggest that 4554W could be a suitable candidate for future therapeutic development against wild-type, and most mutant aSyn aggregation.
Highlights
Neurodegenerative diseases, such as Parkinson’s disease (PD), are associated with the self-assembly and aggregation of proteins (Goedert, 1999)
We report the ability of 4554W to undergo modification through deamidation of the central asparagine residue, occurring on the same timescale as aSyn aggregation in vitro, with peptide modification enhancing its association with aSyn
We report that maximal binding was achieved when 50% of 4554W had undergone deamidation of the Asn 6 residue
Summary
Neurodegenerative diseases, such as Parkinson’s disease (PD), are associated with the self-assembly and aggregation of proteins (Goedert, 1999). They arguably represent one of the most significant challenges to modern medicine; they are prevalent and, as yet, there are no tools available to fight back against the gradual yet relentless progression of neurodegeneration. A range of strategies targeting toxicity associated with protein aggregation are being investigated (Dehay et al, 2015; Fields et al, 2019) These include the use of passive or active immunization (Lee and Lee, 2016; Vaikath et al, 2019). Targeting the aggregation process directly presents an attractive therapeutic option and has been probed using chaperones
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