Researcher ORCID Identifier

0009-0009-3163-4069

Graduation Year

2026

Document Type

Open Access Senior Thesis

Degree Name

Bachelor of Arts

Department

Biochemistry

Reader 1

Bethany Caulkins

Reader 2

Kendra K. Frederick

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Terms of Use for work posted in Scholarship@Claremont.

Rights Information

© 2025 Carah K Allen

Abstract

The aggregation of α-synuclein (α-syn) into amyloid fibrils is a central pathological hallmark of Parkinson’s disease and other related synucleinopathies. Although monomeric α-syn is intrinsically disordered, the protein assembles into multiple fibril polymorphs that differ in their β-sheet core structures. Surrounding each polymorph is the “fuzzy coat,” which is a highly dynamic, intrinsically disordered region (IDR) that is not resolved by high-resolution structural techniques, such as Cryo-EM, but is thought to influence fibril interactions, propagation, and toxicity. Understanding whether different polymorphs maintain distinct fuzzy-coat conformational ensembles is therefore essential for connecting amyloid structure to biological function. To address this question, we examined the conformational ensembles of the N-terminal IDRs of α-syn in three fibril types: wild-type (WT), N-terminally acetylated WT, and N-terminally acetylated A53T. Using solid-state NMR of frozen samples isotopically enriched at glycine, valine, and leucine positions, we analyzed residue-specific chemical shift distributions to infer the populations of α-helical, β-sheet, and coil conformers. Critically, it was found that the fuzzy coat differs across fibril polymorphs. Specifically, residue-specific effects are observed where modifications to α-synuclein strongly increase α-helical dihedral sampling for valine. Contrastingly, modifications increase sampling of β-strand dihedral angles for the single-site leucine. Finally, as expected, glycines broad conformational flexibility allows it to sample most dihedral angles, and was generally found to be insensitive towards modifications to α-synuclein fibrils. Together, these findings demonstrate that the conformational ensemble of the α-syn fuzzy coat is not universal but varies across fibril polymorphs in residue-specific ways. These polymorph-dependent differences offer insight into how structural variations in α-syn fibrils may lead to distinct cellular interactions and pathological outcomes. These insights highlight how targeting polymorph-specific fuzzy-coat interactions may open new avenues for therapeutic intervention in synucleinopathies.

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