Novel in situ seeding immunodetection assay uncovers neuronal-driven alpha-synuclein seeding in Parkinson’s disease
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Aggregates of alpha-synuclein (α-syn) propagate through template-induced misfolding in people with Parkinson’s disease (PD) and Multiple System Atrophy (MSA). Prion-like seeding is crucial in disease initiation and progression, representing a major target for disease-modifying therapies. The detection of α-syn seeding with seeding amplification assays (SAAs) has remarkable diagnostic and research potential. However, current SAAs rely on bulk tissue homogenates or fluids, losing critical spatial and cellular resolution. Here, we report our novel in situ seeding immunodetection (isSID) assay that enables the visualization of seeding with unprecedented morphological detail in intact biological tissue. Using the isSID assay, we confirm seeding activity in α-syn aggregates in PD, MSA, and other proteinopathies, while uncovering neuron-driven seeding preceding the clinical symptom onset in PD. Our findings provide new fundamental insights into the pathogenesis underlying neurodegeneration and establish an invaluable tool for studying protein aggregation dynamics, with potential applications in biomarker discovery, diagnostics, and therapeutics.
Date Issued
2025-08-25
Date Acceptance
2025-08-06
Citation
npj Parkinson's Disease, 2025, 11
ISSN
2373-8057
Publisher
Nature Portfolio
Journal / Book Title
npj Parkinson's Disease
Volume
11
Copyright Statement
© The Author(s) 2025 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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Publication Status
Published
Article Number
259
Date Publish Online
2025-08-25