Otero-Jimenez Maria, Wojewska Marcelina J, Jogaudaite Simona, Miller David, Gray-Rodriguez Sandra, Geoghegan Grainne C, Abelleira-Hervas Laura, Viney Tim James, Sarkany Barbara, Gveric Djordje, Gentleman Steve, Alegre-Abarrategui Javier
Department of Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK.
Imperial College Advanced Hackspace, Imperial College London, London, UK.
NPJ Parkinsons Dis. 2025 Aug 25;11(1):259. doi: 10.1038/s41531-025-01111-y.
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.
在帕金森病（PD）和多系统萎缩（MSA）患者中，α-突触核蛋白（α-syn）聚集体通过模板诱导的错误折叠进行传播。朊病毒样种子形成在疾病的起始和进展中至关重要，是疾病修饰疗法的主要靶点。用种子扩增分析（SAA）检测α-syn种子形成具有显著的诊断和研究潜力。然而，目前的SAA依赖于大块组织匀浆或体液，失去了关键的空间和细胞分辨率。在此，我们报告了我们新颖的原位种子免疫检测（isSID）分析方法，该方法能够在完整的生物组织中以前所未有的形态细节可视化种子形成。使用isSID分析，我们证实了PD、MSA和其他蛋白质病中α-syn聚集体的种子形成活性，同时发现在PD临床症状出现之前存在神经元驱动的种子形成。我们的发现为神经退行性变的发病机制提供了新的基础见解，并建立了一个研究蛋白质聚集动力学的宝贵工具，在生物标志物发现、诊断和治疗方面具有潜在应用价值。
