Molecular properties and diagnostic potential of monoclonal antibodies targeting cytotoxic α-synuclein oligomers.

Autor: Nielsen J; Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus C, Denmark., Lauritsen J; DANDRITE & Department of Biomedicine, Aarhus University, Aarhus C, Denmark., Pedersen JN; Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus C, Denmark., Nowak JS; Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus C, Denmark., Bendtsen MK; Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus C, Denmark., Kleijwegt G; Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus C, Denmark., Lusser K; Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus C, Denmark., Pitarch LC; Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus C, Denmark., Moreno JV; Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus C, Denmark., Schneider MM; Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK., Krainer G; Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.; Institute of Molecular Biosciences, University of Graz, Graz, Austria., Goksøyr L; Centre for Medical Parasitology at the Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark., Khalifé P; Centre for Medical Parasitology at the Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark., Kaalund SS; Centre for Neuroscience and Stereology, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark., Aznar S; Centre for Neuroscience and Stereology, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark., Kjærgaard M; Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, Denmark., Sereikaité V; Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark., Strømgaard K; Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark., Knowles TPJ; Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK., Nielsen MA; Centre for Medical Parasitology at the Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark., Sander AF; Centre for Medical Parasitology at the Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark., Romero-Ramos M; DANDRITE & Department of Biomedicine, Aarhus University, Aarhus C, Denmark. mrr@biomed.au.dk., Otzen DE; Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus C, Denmark. dao@inano.au.dk.; Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, Denmark. dao@inano.au.dk.
Jazyk: angličtina
Zdroj: NPJ Parkinson's disease [NPJ Parkinsons Dis] 2024 Jul 29; Vol. 10 (1), pp. 139. Date of Electronic Publication: 2024 Jul 29.
DOI: 10.1038/s41531-024-00747-6
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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