Development and validation of an expanded antibody toolset that captures alpha-synuclein pathological diversity in Lewy body diseases.

Altay, Melek Firat; Kumar, Senthil T; Burtscher, Johannes; Jagannath, Somanath; Strand, Catherine; Miki, Yasuo; Parkkinen, Laura; Holton, Janice L; Lashuel, Hilal A (2023). Development and validation of an expanded antibody toolset that captures alpha-synuclein pathological diversity in Lewy body diseases. NPJ Parkinson's disease, 9(1), p. 161. Nature Publishing Group 10.1038/s41531-023-00604-y

Preview

Text s41531-023-00604-y.pdf - Published Version Available under License Creative Commons: Attribution (CC-BY). Download (9MB) | Preview

The abnormal aggregation and accumulation of alpha-synuclein (aSyn) in the brain is a defining hallmark of synucleinopathies. Various aSyn conformations and post-translationally modified forms accumulate in pathological inclusions and vary in abundance among these disorders. Relying on antibodies that have not been assessed for their ability to detect the diverse forms of aSyn may lead to inaccurate estimations of aSyn pathology in human brains or disease models. To address this challenge, we developed and characterized an expanded antibody panel that targets different sequences and post-translational modifications along the length of aSyn, and that recognizes all monomeric, oligomeric, and fibrillar aSyn conformations. Next, we profiled aSyn pathology across sporadic and familial Lewy body diseases (LBDs) and reveal heterogeneous forms of aSyn pathology, rich in Serine 129 phosphorylation, Tyrosine 39 nitration and N- and C-terminal tyrosine phosphorylations, scattered both to neurons and glia. In addition, we show that aSyn can become hyperphosphorylated during processes of aggregation and inclusion maturation in neuronal and animal models of aSyn seeding and spreading. The validation pipeline we describe for these antibodies paves the way for systematic investigations into aSyn pathological diversity in the human brain, peripheral tissues, as well as in cellular and animal models of synucleinopathies.

Interest & Impact

Downloads

3 since deposited on 13 Dec 2023
3 in the past 12 months

Citations

5 Citations in Web of Science ®
6 Citations in Scopus

Search

in Google Scholar™

Services

Actions (login required)

Edit item

Actions (login required)

Edit item