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The α-synuclein seed amplification assay: Interpreting a test of Parkinson's pathology

Lookup NU author(s): Dr Daniel ErskineORCiD

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Abstract

The α-synuclein seed amplification assay (αSyn-SAA) sensitively detects Lewy pathology, the amyloid state of α-synuclein, in the cerebrospinal fluid (CSF) of patients with Parkinson's disease (PD). The αSyn-SAA harnesses the physics of seeding, whereby a superconcentrated solution of recombinant α-synuclein lowers the thermodynamic threshold (nucleation barrier) for aggregated α-synuclein to act as a nucleation catalyst ("seed") to trigger the precipitation (nucleation) of monomeric α-synuclein into pathology. This laboratory setup increases the signal for identifying a catalyst if one is present in the tissue examined. The result is binary: positive, meaning precipitation occurred, and a catalyst is present, or negative, meaning no precipitation, therefore no catalyst. Since protein precipitation via seeding can only occur at a concentration many-fold higher than the human brain, laboratory-elicited seeding does not mean human brain seeding. We suggest that a positive αSyn-SAA reveals the presence of pathological α-synuclein but not the underlying etiology for the precipitation of monomeric α-synuclein into its pathological form. Thus, a positive αSyn-SAA supports a clinical diagnosis of PD but cannot inform disease pathogenesis, ascertain severity, predict the rate of progression, define biology or biological subtypes, or monitor treatment response.

Publication metadata

Author(s): Espay AJ, Lees AJ, Cardoso F, Frucht SJ, Erskine D, Sandoval IM, Bernal-Conde LD, Sturchio A, Imarisio A, Hoffman C, Montemagno KT, Milovanovic D, Halliday GM, Manfredsson FP

Publication type: Review

Publication status: Published

Journal: Parkinsonism and Related Disorders

Year: 2025

Volume: 131

Print publication date: 01/02/2025

Online publication date: 27/12/2024

Acceptance date: 26/12/2024

ISSN (print): 1353-8020

ISSN (electronic): 1873-5126

URL: https://doi.org/10.1016/j.parkreldis.2024.107256

DOI: 10.1016/j.parkreldis.2024.107256

PubMed id: 39794217

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