Reducing C-Terminal-Truncated Alpha-Synuclein by Immunotherapy Attenuates Neurodegeneration and Propagation in Parkinson's Disease-Like Models

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 alpha-synuclein (alpha-syn). Recent studies have shown that C-terminus (CT) truncation and propagation of alpha-syn play a role in the pathogenesis of PD/DLB. Therefore, we explored the effect of passive immunization against the CT of alpha-syn in the mThy1-alpha-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 alpha-syn. CT alpha-syn antibodies attenuated synaptic and axonal pathology, reduced the accumulation of CT-truncated alpha-syn (CT-alpha-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-alpha-syn and higher-molecular-weight aggregates. Furthermore, in vitro studies showed that preincubation of recombinant alpha-syn with 1H7 and 5C1 prevented CT cleavage of alpha-syn. In a cell-based system, CT antibodies reduced cell-to-cell propagation of full-length alpha-syn, but not of the CT-alpha-syn that lacked the 118 - 126 aa recognition site needed for antibody binding. Furthermore, the results obtained after lentiviral expression of alpha-syn suggest that antibodies might be blocking the extracellular truncation of alpha-syn by calpain-1. Together, these results demonstrate that antibodies against the CT of alpha-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.