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

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

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54 Scopus citations

Abstract

Parkinson's disease and dementia with Lewy bodies are neurodegenerative disorders characterized by accumulation of α-synuclein (α-syn). Recently, single-chain fragment variables (scFVs) have been developed against individual conformational species of α-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 α-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 α-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 Lewy bodies/Parkinson's disease. Thus, the apoB modification had the effect of both increasing accumulation of the scFV in the brain and directing scFV/α-syn complexes for degradation through the ESCRT pathway, leading to improved therapeutic potential of immunotherapy.

Original languageEnglish (US)
Pages (from-to)1753-1767
Number of pages15
JournalMolecular Therapy
Volume22
Issue number10
DOIs
StatePublished - Jan 1 2014

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ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Spencer, B., Emadi, S., Desplats, P., Eleuteri, S., Michael, S., Kosberg, K., Shen, J., Rockenstein, E., Patrick, C., Adame, A., Gonzalez, T., Sierks, M., & Masliah, E. (2014). ESCRT-mediated uptake and degradation of brain-targeted α-synuclein single chain antibody attenuates neuronal degeneration in vivo. Molecular Therapy, 22(10), 1753-1767. https://doi.org/10.1038/mt.2014.129