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Lipid Acyl Chain-Driven α-Synuclein Fibril Polymorphisms and Neuronal Pathologies
Journal article   Open access   Peer reviewed

Lipid Acyl Chain-Driven α-Synuclein Fibril Polymorphisms and Neuronal Pathologies

Yoongyeong Baek, Anika Alim, Yanheng Dong, Tarek Olabi, Jungwook Paek and Myungwoon Lee
ACS chemical neuroscience
13 Mar 2026
DOI: https://doi.org/10.1021/acschemneuro.5c00730
PMID: 41821508
Featured in Collection :   Research Supported by Drexel Libraries' OA Programs
url
https://doi.org/10.1021/acschemneuro.5c00730View
Published, Version of Record (VoR)Open Access via Drexel Libraries Read and Publish Program 2026CC BY V4.0,  Open

Abstract

Biochemistry & Molecular Biology Chemistry, Medicinal Life Sciences & Biomedicine Neurosciences Neurosciences & Neurology Pharmacology & Pharmacy Science & Technology
Conformational variations in alpha-syn fibrils are thought to underlie the distinct clinical features of synucleinopathies, including Lewy body dementia (LBD), Parkinson's disease (PD), and multiple system atrophy (MSA), suggesting that distinct fibril structures act as molecular fingerprints linked to disease phenotypes. While the origins of these conformational variations remain unclear, increasing evidence points to membranes as key modulators of fibril conformations. In this study, we investigated how age-related alterations in membrane composition and fluidity influence alpha-syn fibril formation and cellular outcomes. Using complex membrane mixtures that mimic normal neuronal membranes and their age-related modifications in fatty acid chains, we found that alpha-syn fibrils grown with these membranes displayed distinct 2D ssNMR spectral patterns compared to lipid-free alpha-syn fibrils, reflecting differences in the rigid fibril cores. Moreover, fibrils grown with age-related membranes exhibited weaker membrane association than those formed with normal neuronal membranes. These membrane-associated fibrils induce stronger neuronal pathologies than lipid-free fibrils, although the severity differed in terms of intraneuronal aggregation and inflammatory responses. Overall, our findings provide new insights into how age-related changes in membrane composition shape alpha-syn fibril structure and pathogenicity, strengthening the link between membrane dynamics and amyloid-driven neurodegeneration.

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