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<p>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 (<i>is</i>SID) assay that enables the visualization of seeding with unprecedented morphological detail in intact biological tissue. Using the <i>is</i>SID 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.</p>

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Novel in situ seeding immunodetection assay uncovers neuronal-driven alpha-synuclein seeding in Parkinson’s disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月25日

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  • Maria Otero-Jimenez,
  • Marcelina J. Wojewska,
  • Simona Jogaudaite,
  • David Miller,
  • Sandra Gray-Rodriguez,
  • Grainne C. Geoghegan,
  • Laura Abelleira-Hervas,
  • Tim James Viney,
  • Barbara Sarkany,
  • Djordje Gveric,
  • Steve Gentleman,
  • Javier Alegre-Abarrategui

摘要

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.