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<p>Α-Synuclein (α-Syn) aggregation and fibrillation are pathological hallmarks of several neurodegenerative disorders, collectively termed synucleinopathies. The misfolded α-Syn protein exhibits a prion-like seeding behavior, promoting misfolding, intracellular spread, and progressive neurodegeneration. Recent advances in structural biology have revealed critical insights into the conformational heterogeneity of α-Syn aggregates and their strain-specific properties across distinct synucleinopathies. In parallel, significant progress has been made in biomarker development, particularly with the arrival of seed amplification assays. Among these, Real-Time Quaking-Induced Conversion (RT-QuIC) has emerged as a highly sensitive, specific, and scalable method for detecting pathogenic α-Syn species in cerebrospinal fluid and other tissues. This review summarizes the latest findings from structural studies on α-Syn oligomers and aggregates, their relevance to disease mechanisms, and highlights RT-QuIC as the most clinically advanced and rapidly evolving assay. We discuss its potential for early, biomarker-driven diagnostics, patient stratification, and clinical implementation.</p>

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When Proteins Go MAD—Misfolded, Amplified, Detected: Advances in α-Synuclein Pathophysiology and RT-QuIC Detection

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月9日

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  • Naďa Labajová,
  • Adam Polák,
  • Ondrej Cehlár,
  • Pavle Križan,
  • Jozef Hritz,
  • Martin Kolisek,
  • Matej Škorvánek,
  • Rostislav Škrabana,
  • Branislav Kovačech,
  • Norbert Žilka

摘要

Α-Synuclein (α-Syn) aggregation and fibrillation are pathological hallmarks of several neurodegenerative disorders, collectively termed synucleinopathies. The misfolded α-Syn protein exhibits a prion-like seeding behavior, promoting misfolding, intracellular spread, and progressive neurodegeneration. Recent advances in structural biology have revealed critical insights into the conformational heterogeneity of α-Syn aggregates and their strain-specific properties across distinct synucleinopathies. In parallel, significant progress has been made in biomarker development, particularly with the arrival of seed amplification assays. Among these, Real-Time Quaking-Induced Conversion (RT-QuIC) has emerged as a highly sensitive, specific, and scalable method for detecting pathogenic α-Syn species in cerebrospinal fluid and other tissues. This review summarizes the latest findings from structural studies on α-Syn oligomers and aggregates, their relevance to disease mechanisms, and highlights RT-QuIC as the most clinically advanced and rapidly evolving assay. We discuss its potential for early, biomarker-driven diagnostics, patient stratification, and clinical implementation.