Journal Article

Propagative α-synuclein seeds as serum biomarkers for synucleinopathies

Kondo, Akihide, Imamichi-Tatano, Yoko, Saiki, Shinji, Okuzumi, Ayami, Fukuhara, Takeshi, McIntyre, Deborah, Ueno, Shin-ichi, Nojiri, Shuko, Gérardy, Jean-Jacques, Taniguchi, Daisuke, Nukina, Nobuyuki, Li, Yuanzhe, Tsunemi, Taiji, Funayama, Manabu, Hattori, Nobutaka, Kruger, Rejko, Matsumoto, Gen, Hatano, Taku, Mittelbronn, Michel, Kakuta, Soichiro, Kimura, Haruka, Uchiyama, Yasuo

2023

Overview

Abnormal α-synuclein aggregation is a key pathological feature of a group of neurodegenerative diseases known as synucleinopathies, which include Parkinson’s disease (PD), dementia with Lewy bodies and multiple system atrophy (MSA). The pathogenic β-sheet seed conformation of α-synuclein is found in various tissues, suggesting potential as a biomarker, but few studies have been able to reliably detect these seeds in serum samples. In this study, we developed a modified assay system, called immunoprecipitation-based real-time quaking-induced conversion (IP/RT-QuIC), which enables the detection of pathogenic α-synuclein seeds in the serum of individuals with synucleinopathies. In our internal first and second cohorts, IP/RT-QuIC showed high diagnostic performance for differentiating PD versus controls (area under the curve (AUC): 0.96 (95% confidence interval (CI) 0.95–0.99)/AUC: 0.93 (95% CI 0.84–1.00)) and MSA versus controls (AUC: 0.64 (95% CI 0.49–0.79)/AUC: 0.73 (95% CI 0.49–0.98)). IP/RT-QuIC also showed high diagnostic performance in differentiating individuals with PD (AUC: 0.86 (95% CI 0.74–0.99)) and MSA (AUC: 0.80 (95% CI 0.65–0.97)) from controls in a blinded external cohort. Notably, amplified seeds maintained disease-specific properties, allowing the differentiation of samples from individuals with PD versus MSA. In summary, here we present a novel platform that may allow the detection of individuals with synucleinopathies using serum samples. A modified seed aggregation assay detects minute amounts of serum α-synuclein seeds in individuals with synucleinopathy, demonstrating high performance as a diagnostic biomarker.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/378/87 / 692/617/375/346/1718 / alpha-Synuclein / Atrophy / Biomarkers / Biomedical and Life Sciences / Biomedicine / Cancer Research / Conformation / Dementia disorders / Diagnostic systems / Humans / Immunoprecipitation / Infectious Diseases / Lewy bodies / Lewy Body Disease - diagnosis / Metabolic Diseases / Molecular Medicine / Movement disorders / Multiple System Atrophy - diagnosis / Neurodegenerative diseases / Neurosciences / Parkinson Disease - diagnosis / Parkinson's disease / Seeds / Synuclein / Synucleinopathies - pathology