Designer D-peptides targeting the N-terminal region of α-synuclein to prevent parkinsonian-associated fibrilization and cytotoxicity

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dc.contributor.authorHorsley, J.R.
dc.contributor.authorJovcevski, B.
dc.contributor.authorPukala, T.L.
dc.contributor.authorAbell, A.D.
dc.date.issued2022
dc.description.abstractThe deposition of α-synuclein (αS) aggregates in the gut and the brain is ever present in cases of Parkinson’s disease. While the central non-amyloidogenic-component (NAC) region of αS plays a critical role in fibrilization, recent studies have identified a specific sequence from within the N-terminal region (NTR, residues 36–42) as a key modulator of αS fibrilization. Due to the lack of effective therapeutics which specifically target αS aggregates, we have developed a strategy to prevent the aggregation and subsequent toxicity attributed to αS fibrilization utilizing NTR targeting peptides. In this study, L- and D-isoforms of a hexa- (VAQKTV-Aib, 77–82 NAC) and heptapeptide (GVLYVGS-Aib, 36–42 NTR) containing a self-recognition component unique to αS, as well as a Cterminal disruption element, were synthesized to target primary sequence regions of αS that modulate fibrilization. The D-peptide that targets the NTR (NTR-TP-D) was shown by ThT fluorescence assays and TEM to be the most effective at preventing fibril formation and elongation, as well as increasing the abundance of soluble monomeric αS. In addition, NTR-TP-D alters the conformation of destabilised monomers into a less aggregationprone state and reduces the hydrophobicity of αS fibrils via fibril remodelling. Furthermore, both NTR-TP isoforms alleviate the cytotoxic effects of αS aggregates in both Neuro-2a and Caco-2 cells. Together, this study highlights how targeting the NTR of αS using D-isoform peptide inhibitors may effectively combat the deleterious effects of αS fibrilization and paves the way for future drug design to utilise such an approach to treat Parkinson’s disease.
dc.description.statementofresponsibilityJohn R. Horsley, Blagojce Jovcevski, Tara L. Pukala, Andrew D. Abell
dc.identifier.citationBBA: Proteins and Proteomics, 2022; 1870(10):140826-1-140826-9
dc.identifier.doi10.1016/j.bbapap.2022.140826
dc.identifier.issn1570-9639
dc.identifier.issn1878-1454
dc.identifier.orcidJovcevski, B. [0000-0001-7999-1385]
dc.identifier.orcidPukala, T.L. [0000-0001-7391-1436]
dc.identifier.orcidAbell, A.D. [0000-0002-0604-2629]
dc.identifier.urihttps://hdl.handle.net/2440/136661
dc.language.isoen
dc.publisherElsevier BV
dc.relation.granthttp://purl.org/au-research/grants/arc/DP170102033
dc.relation.granthttp://purl.org/au-research/grants/arc/DP180101581
dc.rights© 2022 Elsevier B.V. All rights reserved.
dc.source.urihttps://doi.org/10.1016/j.bbapap.2022.140826
dc.subjectα-Synuclein; Amyloid fibrils; Protein aggregation; Peptide inhibitors; Drug design
dc.subject.meshBrain
dc.subject.meshCaco-2 Cells
dc.subject.meshHumans
dc.subject.meshParkinson Disease
dc.subject.meshPeptides
dc.subject.meshalpha-Synuclein
dc.titleDesigner D-peptides targeting the N-terminal region of α-synuclein to prevent parkinsonian-associated fibrilization and cytotoxicity
dc.typeJournal article
pubs.publication-statusPublished

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