Abstract
Synucleinopathies are a spectrum of neurodegenerative diseases characterized by the intracellular deposition of the protein α-synuclein leading to multiple outcomes, including dementia and Parkinsonism. Recent findings support the notion that across the spectrum of synucleinopathies there exist diverse but specific biochemical modifications and/or structural conformations of α-synuclein, which would give rise to protein strain specific prion-like intercellular transmission, a proposed model that could explain synucleinopathies disease progression. Herein, we characterized a panel of antibodies with epitopes within both the C- and N- termini of α-synuclein. A comprehensive analysis of human pathological tissue and mouse models of synucleinopathy with these antibodies support the notion that α-synuclein exists in distinct modified forms and/or structural variants. Furthermore, these well-characterized and specific tools allow the investigation of biochemical changes associated with α-synuclein inclusion formation. We have identified several antibodies of interest with diverse staining and epitope properties that will prove useful in future investigations of strain specific disease progression and the development of targeted immunotherapeutic approaches to synucleinopathies.
Highlights
Data Availability Statement: All relevant data are within the paper and its Supporting Information files
Recombinant 21–140 human αS with an ATG codon added at the amino-terminus followed by the nucleotide sequence for residues 244–372 in 4R human tau followed by human Aβ1–42 designated 21–140 αS/K18/Aβ1–42 was purified using a HiTrap Q HP column (GE Healthcare Life Sciences) followed by size exclusion chromatography
Protein concentrations were determined by bicinchoninic acid (BCA) assay using bovine serum albumin (BSA; Pierce, Rockford, IL) as a standard
Summary
Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Some recent studies suggest that the mechanism(s) involved in the intercellular transmission of αS aggregates may result from the generation of unique αS cleavage products that may contribute to the spread of pathology [17,18]. Overall, these findings indicate a clear need for well characterized tools capable of assessing various forms of processed αS. We describe and characterize a novel series of αS antibodies with epitopes specific for various amino and carboxy regions of αS protein We demonstrate that these antibodies show marked differences in their ability to recognize pathological αS inclusions in human synucleinopathies and various animal models. Such differential neuropathological attributes support the notion that subtle variations in misfolded αS protein or αS strains may serve as signatures in the spectrum of synucleinopathies
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