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

Alberto J. Espay, James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH, USA. Electronic address: aespay@gmail.com.
Andrew J. Lees, The National Hospital, Queen Square and Reta Lila Weston Institute for Neurological Studies University College London, London, UK.
Francisco Cardoso, Movement Disorders Unit, Neurology Service, Internal Medicine Department, The Federal University of Minas Gerais, Belo Horizonte, Brazil.
Steven J. Frucht, The Marlene and Paolo Fresco Institute for Parkinson's and Movement Disorders, New York University Langone Health, New York, NY, USA.
Daniel Erskine, Translational and Clinical Research Institute, Newcastle University, UK.
Ivette M. Sandoval, Department of Translational Neuroscience and the Muhammad Ali Parkinson Center, Barrow Neurological Institute, Phoenix, AZ, USA.
Luis Daniel Bernal-Conde, Department of Translational Neuroscience and the Muhammad Ali Parkinson Center, Barrow Neurological Institute, Phoenix, AZ, USA.
Andrea Sturchio, James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH, USA; Laboratory of Translational Neuropharmacology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Alberto Imarisio, Department of Molecular Medicine, University of Pavia, 27100, Pavia, Italy; Neurogenetics Research Centre, IRCCS Mondino Foundation, 27100, Pavia, Italy.
Christian Hoffmann, Laboratory of Molecular Neuroscience, German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.
Kora T. Montemagno, Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark.
Dragomir Milovanovic, Laboratory of Molecular Neuroscience, German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany; Einstein Center for Neuroscience, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, 10117, Berlin, Germany.
Glenda M. Halliday, School of Medical Sciences, Faculty of Medicine and Health and the Brain and Mind Centre, University of Sydney, Camperdown, New South Wales, 2050, Australia.
Fredric P. Manfredsson, Department of Translational Neuroscience and the Muhammad Ali Parkinson Center, Barrow Neurological Institute, Phoenix, AZ, USA.

Document Type

Article

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.

Keywords

Parkinson's disease, Seed amplification assay, Seeding, α-synuclein

Medical Subject Headings

Humans; alpha-Synuclein (cerebrospinal fluid, metabolism); Parkinson Disease (cerebrospinal fluid, pathology, diagnosis)

Publication Date

2-1-2025

Publication Title

Parkinsonism & related disorders

E-ISSN

1873-5126

Volume

131

First Page

107256

PubMed ID

39794217

Digital Object Identifier (DOI)

10.1016/j.parkreldis.2024.107256

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