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Article

Evaluation of the Effect of β-Wrapin AS69 in a Mouse Model Based on Alpha-Synuclein Overexpression

by
Lennart Höfs
1,2,
David Geißler-Lösch
1,2,
Kristof M. Wunderlich
1,2,
Eva M. Szegö
1,2,
Chris Van den Haute
3,4,
Veerle Baekelandt
3,4,
Wolfgang Hoyer
5,6 and
Björn H. Falkenburger
1,2,*
1
Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany
2
Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 01307 Dresden, Germany
3
Leuven Viral Vector Core, KU Leuven, 3000 Leuven, Belgium
4
Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium
5
Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
6
Institute of Biological Information Processing (IBI-7), Forschungszentrum Jülich GmbH, 52428 Jülich, Germany
*
Author to whom correspondence should be addressed.
Biomolecules 2024, 14(7), 756; https://doi.org/10.3390/biom14070756
Submission received: 1 May 2024 / Revised: 3 June 2024 / Accepted: 19 June 2024 / Published: 25 June 2024
(This article belongs to the Special Issue Synuclein Proteins, 2nd Edition)
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Abstract

Aggregation of the protein α-Synuclein (αSyn) is a hallmark of Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple systems atrophy, and alleviating the extent of αSyn pathology is an attractive strategy against neurodegeneration. The engineered binding protein β-wrapin AS69 binds monomeric αSyn. AS69 reduces primary and secondary nucleation as well as fibril elongation in vitro. It also mitigates aSyn pathology in a mouse model based on intrastriatal injection of aSyn pre-formed fibrils (PFFs). Since the PFF-based model does not represent all aspects of PD, we tested here whether AS69 can reduce neurodegeneration resulting from αSyn overexpression. Human A53T-αSyn was overexpressed in the mouse Substantia nigra (SN) by using recombinant adeno-associated viral vector (rAAV). AS69 was also expressed by rAAV transduction. Behavioral tests and immunofluorescence staining were used as outcomes. Transduction with rAAV-αSyn resulted in αSyn pathology as reported by phospho-αSyn staining and caused degeneration of dopaminergic neurons in the SN. The co-expression of rAAV-AS69 did not reduce αSyn pathology or the degeneration of dopaminergic neurons. We conclude that αSyn monomer binding by rAAV-AS69 was insufficient to protect from aSyn pathology resulting from αSyn overexpression.
Keywords: α-Synuclein; alpha-Synuclein; Parkinson’s disease; PD; AS69; β-wrapin; aggregation inhibitors; amyloid aggregation inhibitors; recombinant adeno-associated viral vector; rAAV; synuclein overexpression; Substantia nigra; mouse model; in vivo α-Synuclein; alpha-Synuclein; Parkinson’s disease; PD; AS69; β-wrapin; aggregation inhibitors; amyloid aggregation inhibitors; recombinant adeno-associated viral vector; rAAV; synuclein overexpression; Substantia nigra; mouse model; in vivo

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MDPI and ACS Style

Höfs, L.; Geißler-Lösch, D.; Wunderlich, K.M.; Szegö, E.M.; Van den Haute, C.; Baekelandt, V.; Hoyer, W.; Falkenburger, B.H. Evaluation of the Effect of β-Wrapin AS69 in a Mouse Model Based on Alpha-Synuclein Overexpression. Biomolecules 2024, 14, 756. https://doi.org/10.3390/biom14070756

AMA Style

Höfs L, Geißler-Lösch D, Wunderlich KM, Szegö EM, Van den Haute C, Baekelandt V, Hoyer W, Falkenburger BH. Evaluation of the Effect of β-Wrapin AS69 in a Mouse Model Based on Alpha-Synuclein Overexpression. Biomolecules. 2024; 14(7):756. https://doi.org/10.3390/biom14070756

Chicago/Turabian Style

Höfs, Lennart, David Geißler-Lösch, Kristof M. Wunderlich, Eva M. Szegö, Chris Van den Haute, Veerle Baekelandt, Wolfgang Hoyer, and Björn H. Falkenburger. 2024. "Evaluation of the Effect of β-Wrapin AS69 in a Mouse Model Based on Alpha-Synuclein Overexpression" Biomolecules 14, no. 7: 756. https://doi.org/10.3390/biom14070756

APA Style

Höfs, L., Geißler-Lösch, D., Wunderlich, K. M., Szegö, E. M., Van den Haute, C., Baekelandt, V., Hoyer, W., & Falkenburger, B. H. (2024). Evaluation of the Effect of β-Wrapin AS69 in a Mouse Model Based on Alpha-Synuclein Overexpression. Biomolecules, 14(7), 756. https://doi.org/10.3390/biom14070756

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