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Journal article
Lipid Acyl Chain-Driven α-Synuclein Fibril Polymorphisms and Neuronal Pathologies
ACS chemical neuroscience
13 Mar 2026
PMID: 41821508
Featured in Collection : Research Supported by Drexel Libraries' OA Programs
Abstract
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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Details
- Title
- Lipid Acyl Chain-Driven α-Synuclein Fibril Polymorphisms and Neuronal Pathologies
- Creators
- Yoongyeong Baek - Drexel University, ChemistryAnika Alim - Binghamton UniversityYanheng Dong - Binghamton UniversityTarek Olabi - Drexel UniversityJungwook Paek - Binghamton UniversityMyungwoon Lee (Corresponding Author) - Drexel University, Chemistry
- Publication Details
- ACS chemical neuroscience
- Publisher
- Amer Chemical Soc
- Number of pages
- 17
- Grant note
- DMR-2128556 / Division of Materials Research; National Science Foundation (NSF); NSF - Directorate for Mathematical & Physical Sciences (MPS) NA / State of Florida NS139178 / All of Us Research Program
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology; Chemistry
- Web of Science ID
- WOS:001714897900001
- Scopus ID
- 2-s2.0-105034921439
- Other Identifier
- 991022170455504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Medicinal
- Neurosciences