ESCRT-mediated Uptake and Degradation of Brain-targeted alpha-synuclein Single Chain Antibody Attenuates Neuronal Degeneration In Vivo

作者：Spencer Brian; Emadi Sharareh; Desplats Paula; Eleuteri Simona; Michael Sarah; Ko**erg Kori; Shen Jay; Rockenstein Edward; Patrick Christina; Adame Anthony; Gonzalez Tania; Sierks Michael; Masliah Eliezer^*

来源：Molecular Therapy, 2014, 22(10): 1753-1767.

DOI：10.1038/mt.2014.129

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.

• 出版日期2014-10