期刊
MOLECULAR THERAPY
卷 22, 期 10, 页码 1753-1767出版社
CELL PRESS
DOI: 10.1038/mt.2014.129
关键词
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资金
- National Institutes of Health [AG18440, AG022074]
- Michael J. Fox Foundation [NS057096]
Parkinson's disease and dementia with Lewy bodies are neurodegenerative disorders characterized by accumulation of a-synuclein (alpha-syn). Recently, single-chain fragment variables (scFVs) have been developed against individual conformational species of a-syn. Unlike more traditional monoclonal antibodies, these scFVs will not activate or be endocytosed by Fc receptors. For this study, we investigated an scFV directed against oligomeric a-syn fused to the LDL receptor-binding domain from apolipoprotein B (apoB). The modified scFV showed enhanced brain penetration and was imported into neuronal cells through the endosomal sorting complex required for transport (ESCRT) pathway, leading to lysosomal degradation of alpha-syn aggregates. Further analysis showed that the scFV was effective at ameliorating neurodegenerative pathology and behavioral deficits observed in the mouse model of dementia with Le bodies/Parkinson's disease. Thus, the apoB modification had the effect of both increasing accumulation of the scFV in the brain and directing scFV/alpha-syn complexes for degradation through the ESCRT pathway, leading to improved therapeutic potential of immunotherapy.
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