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ESCRT mediated uptake and degradation of brain targeted ?-synuclein-single chain antibody attenuates neuronal degeneration in vivo.

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Mol Ther 2014 Jul;

Authors: Brian Spencer, Sharareh Emadi, Paula Desplats, Simona Eleuteri, Sarah Michael, Kori Kosberg, Jay Shen, Edward Rockenstein, Christina Patrick, Anthony Adame, Tania Gonzalez, Michael Sierks, Eliezer Masliah

Parkinson's disease and Dementia with Lewy bodies are neurodegenerative disorders characterized by accumulation of ?-synuclein. Recently, single chain antibodies (scFV) have been developed against individual conformational species of ?-syn. Unlike more traditional mAbs, these scFVs will not activate or be endocytosed by Fc receptors. For this study, we investigated a scFV directed against oligomeric ?-syn fused to the LDL receptor-binding domain from apoB. The modified scFV showed enhanced brain penetration and was imported into neuronal cells through the ESCRT pathway leading to lysosomal degradation of ?-syn aggregates. Further analysis showed the scFV was effective at ameliorating neurodegenerative pathology and behavioral deficits observed in the mouse model of DLB/PD. Thus the apoB modification had the effect of both increasing accumulation of the scFV in the brain and directing scFV/ ?-syn complexes for degradation through the ESCRT pathway leading to improved therapeutic potential of immunotherapy.Molecular Therapy (2014); doi:10.1038/mt.2014.129.

PMID: 25008355 [PubMed - as supplied by publisher]

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