Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson's disease-like models

• Published in: The Journal of neuroscience Vol. 34; no. 28; pp. 9441 - 9454
• Main Authors: Games, Dora, Valera, Elvira, Spencer, Brian, Rockenstein, Edward, Mante, Michael, Adame, Anthony, Patrick, Christina, Ubhi, Kiren, Nuber, Silke, Sacayon, Patricia, Zago, Wagner, Seubert, Peter, Barbour, Robin, Schenk, Dale, Masliah, Eliezer
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 09.07.2014
• Subjects: alpha-Synuclein - immunology; Animals; Antibodies, Monoclonal - therapeutic use; Brain - drug effects; Brain - immunology; Disease Models, Animal; Humans; Immunotherapy - methods; Mice; Mice, Transgenic; Movement Disorders - immunology; Movement Disorders - therapy; Parkinsonian Disorders - immunology; Parkinsonian Disorders - therapy; Tissue Distribution; Treatment Outcome; calpain; Parkinson's disease; α-synuclein; immunotherapy; α-synuclein propagation; α-synuclein truncation
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.5314-13.2014

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are common neurodegenerative disorders of the aging population, characterized by progressive and abnormal accumulation of α-synuclein (α-syn). Recent studies have shown that C-terminus (CT) truncation and propagation of α-syn play a role in the pathogenesis of PD/DLB. Therefore, we explored the effect of passive immunization against the CT of α-syn in the mThy1-α-syn transgenic (tg) mouse model, which resembles the striato-nigral and motor deficits of PD. Mice were immunized with the new monoclonal antibodies 1H7, 5C1, or 5D12, all directed against the CT of α-syn. CT α-syn antibodies attenuated synaptic and axonal pathology, reduced the accumulation of CT-truncated α-syn (CT-α-syn) in axons, rescued the loss of tyrosine hydroxylase fibers in striatum, and improved motor and memory deficits. Among them, 1H7 and 5C1 were most effective at decreasing levels of CT-α-syn and higher-molecular-weight aggregates. Furthermore, in vitro studies showed that preincubation of recombinant α-syn with 1H7 and 5C1 prevented CT cleavage of α-syn. In a cell-based system, CT antibodies reduced cell-to-cell propagation of full-length α-syn, but not of the CT-α-syn that lacked the 118-126 aa recognition site needed for antibody binding. Furthermore, the results obtained after lentiviral expression of α-syn suggest that antibodies might be blocking the extracellular truncation of α-syn by calpain-1. Together, these results demonstrate that antibodies against the CT of α-syn reduce levels of CT-truncated fragments of the protein and its propagation, thus ameliorating PD-like pathology and improving behavioral and motor functions in a mouse model of this disease.