PT  - JOURNAL ARTICLE
AU  - Games, Dora
AU  - Valera, Elvira
AU  - Spencer, Brian
AU  - Rockenstein, Edward
AU  - Mante, Michael
AU  - Adame, Anthony
AU  - Patrick, Christina
AU  - Ubhi, Kiren
AU  - Nuber, Silke
AU  - Sacayon, Patricia
AU  - Zago, Wagner
AU  - Seubert, Peter
AU  - Barbour, Robin
AU  - Schenk, Dale
AU  - Masliah, Eliezer
TI  - Reducing C-Terminal-Truncated Alpha-Synuclein by Immunotherapy Attenuates Neurodegeneration and Propagation in Parkinson's Disease-Like Models
AID  - 10.1523/JNEUROSCI.5314-13.2014
DP  - 2014 Jul 09
TA  - The Journal of Neuroscience
PG  - 9441--9454
VI  - 34
IP  - 28
4099  - http://www.jneurosci.org/content/34/28/9441.short
4100  - http://www.jneurosci.org/content/34/28/9441.full
SO  - J. Neurosci.2014 Jul 09; 34
AB  - 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.