Molecular properties and diagnostic potential of monoclonal antibodies targeting cytotoxic α-synuclein oligomers
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α-Synuclein (α-syn) accumulates as insoluble amyloid but also forms soluble α-syn oligomers (αSOs), thought to be even more cytotoxic than fibrils. To detect and block the unwanted activities of these αSOs, we have raised 30 monoclonal antibodies (mAbs) against different forms of αSOs, ranging from unmodified αSOs to species stabilized by lipid peroxidation products and polyphenols, αSOs formed by C-terminally truncated α-syn, and multivalent display of α-syn on capsid virus-like particles (cVLPs). While the mAbs generally show a preference for αSOs, they also bind fibrils, but to variable extents. Overall, we observe great diversity in the mAbs’ relative affinities for monomers and αSOs, varied requirements for the C-terminal extension of α-syn, and only a modest effect on α-syn fibrillation. Several mAbs show several orders of magnitude preference for αSOs over monomers in in-solution studies, while the commercial antibody MJF14 only bound 10-fold more strongly to αSOs than monomeric α-syn. Gratifyingly, seven mAbs almost completely block αSO permeabilization of membrane vesicles. Five selected mAbs identified α-syn-related pathologies like Lewy bodies (LBs) and Lewy Neurites, as well as Glial Cytoplasmic Inclusions in postmortem brains from people diagnosed for PD, dementia with LBs or multiple system atrophy, although to different extents. Three mAbs were particularly useful for pathological evaluation of postmortem brain human tissue, including early stages of PD. Although there was no straightforward connection between the mAbs’ biophysical and immunohistochemical properties, it is encouraging that this comprehensive collection of mAbs able to recognize different aggregated α-syn species in vitro also holds diagnostic potential.
Originalsprog | Engelsk |
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Artikelnummer | 139 |
Tidsskrift | npj Parkinson's Disease |
Vol/bind | 10 |
Udgave nummer | 1 |
Antal sider | 26 |
DOI | |
Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:
This work has generously been funded by the Lundbeck Foundation (grant no. R276-2018-671) as well as the Carlsberg Foundation (grants no. CF19-0337 and CF20-0610). We warmly thank Dr. Mette Malle for help with vesicle preparation, Dr. Henrik Jensen from FIDAbio for his constant and constructive input regarding FIDA analysis, Dr. Jakob Hauge Mikkelsen for his excellent contributions to SPR, and Pia Pedersen and Gitte Ulbjerg Toft for technical assistance and guidance with immunohistochemical staining of post-mortem human and rodent brain tissue.
Publisher Copyright:
© The Author(s) 2024.
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