Anti-α-synuclein c-terminal antibodies block PFF uptake and accumulation of phospho-synuclein in preclinical models of Parkinson's disease

• Published in: Neurobiology of disease 2023-02, Vol.177, p.105969, Article 105969
• Main Authors: Brendza, Robert, Gao, Xiaoying, Stark, Kimberly L., Lin, Han, Lee, Seung-Hye, Hu, Changyun, Cai, Hao, DiCara, Danielle, Hsiao, Yi-Chun, Ngu, Hai, Foreman, Oded, Baca, Miriam, Dohse, Monika, Fortin, Jean-Phillipe, Corpuz, Racquel, Seshasayee, Dhaya, Easton, Amy, Ayalon, Gai, Hötzel, Isidro, Chih, Ben
• Format: Article
• Language: English
• Subjects: Alpha synuclein; alpha-Synuclein - metabolism; Animals; Antibody; Dopaminergic Neurons - metabolism; Mice; Neurodegenerative Diseases - metabolism; Parkinson Disease - metabolism; Parkinson's disease; PFF spreading model; Synucleinopathies - pathology
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2022.105969

Parkinson's disease (PD), a neurodegenerative disease affecting dopaminergic (DA) neurons, is characterized by decline of motor function and cognition. Dopaminergic cell loss is associated with accumulation of toxic alpha synuclein aggregates. As DA neuron death occurs late in the disease, therapeutics that block the spread of alpha synuclein may offer functional benefit and delay disease progression. To test this hypothesis, we generated antibodies to the C terminal region of synuclein with high nanomolar affinity and characterized them in in vitro and in vivo models of spread. Interestingly, we found that only antibodies with high affinity to the distal most portion of the C-terminus robustly reduced uptake of alpha synuclein preformed fibrils (PFF) and accumulation of phospho (S129) alpha synuclein in cell culture. Additionally, the antibody treatment blocked the spread of phospho (S129) alpha synuclein associated-pathology in a mouse model of synucleinopathy. Blockade of neuronal PFF uptake by different antibodies was more predictive of in vivo activity than their binding potency to monomeric or oligomeric forms of alpha synuclein. These data demonstrate that antibodies directed to the C-terminus of the alpha synuclein have differential effects on target engagement and efficacy. Furthermore, our data provides additional support for the development of alpha synuclein antibodies as a therapeutic strategy for PD patients. •Lewy bodies and neurites composed of aggregated alpha synuclein protein are the hallmarks of Parkinson's disease.•Preformed fibrils of alpha-synuclein can seed recruitment of endogenous synuclein into aggregates and spread from cell to cell.•Preformed fibrils of alpha synuclein bind to neurons , are taken up into the cells, causing phosphorylation of alpha synuclein.•In vitro screening identified anti-alpha synuclein antibodies that block uptake of PFFs into neurons also bind to the c-terminus of alpha synuclein.•High affinity c-terminal-targeting antibodies blocked alpha synuclein spread in vivo.