RT Journal Article
SR Electronic
T1 Reducing C-Terminal-Truncated Alpha-Synuclein by Immunotherapy Attenuates Neurodegeneration and Propagation in Parkinson's Disease-Like Models
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 9441
OP 9454
DO 10.1523/JNEUROSCI.5314-13.2014
VO 34
IS 28
A1 Games, Dora
A1 Valera, Elvira
A1 Spencer, Brian
A1 Rockenstein, Edward
A1 Mante, Michael
A1 Adame, Anthony
A1 Patrick, Christina
A1 Ubhi, Kiren
A1 Nuber, Silke
A1 Sacayon, Patricia
A1 Zago, Wagner
A1 Seubert, Peter
A1 Barbour, Robin
A1 Schenk, Dale
A1 Masliah, Eliezer
YR 2014
UL http://www.jneurosci.org/content/34/28/9441.abstract
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.