Recursive Seed Amplification Detects Distinct α-synuclein Strains in Cerebrospinal Fluid of Patients with Parkinson's Disease

Overview

Journal Acta Neuropathol Commun

Publisher Biomed Central

Date 2025 Jan 20

PMID 39833972

Authors

Stefan Brauer

Inaki Schniewind

Elisabeth Dinter

Bjorn H Falkenburger

Affiliations

Soon will be listed here.

Abstract

Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder with a wide range of clinical phenotypes. Pathologically, it is characterized by neuronal inclusions containing misfolded, fibrillar alpha-synuclein (aSyn). Prion-like properties of aSyn contribute to the spread of aSyn pathology throughout the nervous system as the disease progresses. Utilizing these properties, seed amplification assays (SAA) enable the detection of aSyn pathology in living patients. We hypothesized that structurally distinct aSyn aggregates, or strains, may underlie the clinical heterogeneity of PD. To test this hypothesis, we recursively amplified aSyn fibrils from the cerebrospinal fluid (CSF) of 54 patients (34 people with PD and 20 controls). These fibrils were then characterized regarding SAA kinetic properties and detergent resistance. In addition, cultured cells were transfected with SAA products, and the extent of seeded aSyn pathology was quantified by staining for phosphorylated aSyn followed by automated high-throughput microscopy and image analysis. We found that fibrils, amplified from CSF by recursive SAA, exhibit two types of distinct biophysical properties and have different seeding capacities in cells. These properties are associated with clinical parameters and may therefore help explain the clinical heterogeneity in PD. Measuring aSyn strains may be relevant for prognosis and for therapies targeting aSyn pathology.

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