Monoclonal antibodies selective for α-synuclein oligomers/protofibrils recognize brain pathology in Lewy body disorders and α-synuclein transgenic mice with the disease-causing A30P mutation.
Inclusions of intraneuronal alpha-synuclein (α-synuclein) can be detected in brains of patients with Parkinson's disease and dementia with Lewy bodies. The aggregation of α-synuclein is a central feature of the disease pathogenesis. Among the different α-synuclein species, large oligomers/protofibrils have particular neurotoxic properties and should therefore be suitable as both therapeutic and diagnostic targets. Two monoclonal antibodies, mAb38F and mAb38E2, with high affinity and strong selectivity for large α-synuclein oligomers were generated. These antibodies, which do not bind amyloid-beta or tau, recognize Lewy body pathology in brains from patients with Parkinson's disease and dementia with Lewy bodies and detect pathology earlier in α-synuclein transgenic mice than linear epitope antibodies. An oligomer-selective sandwich ELISA, based on mAb38F, was set up to analyze brain extracts of the transgenic mice. The overall levels of α-synuclein oligomers/protofibrils were found to increase with age in these mice, although the levels displayed a large interindividual variation. Upon subcellular fractionation, higher levels of α-synuclein oligomers/protofibrils could be detected in the endoplasmic reticulum around the age when behavioral disturbances develop. In summary, our novel oligomer-selective α-synuclein antibodies recognize relevant pathology and should be important tools to further explore the pathogenic mechanisms in Lewy body disorders. Moreover, they could be potential candidates both for immunotherapy and as reagents in an assay to assess a potential disease biomarker.
Department of Public Health and Caring Sciences, Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Therese
T
Fagerqvist
Veronica
V
Lindström
Eva
E
Nordström
Anna
A
Lord
Stina M E
SM
Tucker
Xingjian
X
Su
Charlotte
C
Sahlin
Alex
A
Kasrayan
Jessica
J
Andersson
Hedvig
H
Welander
Thomas
T
Näsström
Mats
M
Holmquist
Heinrich
H
Schell
Philipp J
PJ
Kahle
Hannu
H
Kalimo
Christer
C
Möller
Pär
P
Gellerfors
Lars
L
Lannfelt
Joakim
J
Bergström
Martin
M
Ingelsson
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015153:Blotting, Western; D001921:Brain / Q000473:pathology*; D018076:DNA, Complementary / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes; D005561:Formates / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D020961:Lewy Body Disease / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics / Q000502:physiology; D013347:Subcellular Fractions / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics* / Q000276:immunology*
D000911:Antibodies, Monoclonal; D018076:DNA, Complementary; D000939:Epitopes; D005561:Formates; D051844:alpha-Synuclein; C030544:formic acid