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

Mol Ther. 2014 Oct;22(10):1753-67. doi: 10.1038/mt.2014.129. Epub 2014 Jul 10.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Apolipoproteins B / chemistry
  • Apolipoproteins B / metabolism
  • Autophagy
  • Behavior, Animal
  • Brain / metabolism*
  • Brain / pathology
  • Cell Line
  • Endosomal Sorting Complexes Required for Transport / genetics
  • Endosomal Sorting Complexes Required for Transport / metabolism*
  • Gene Order
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics
  • Lentivirus / genetics
  • Mice
  • Mice, Transgenic
  • Nerve Degeneration / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Protein Binding
  • Protein Transport
  • Proteolysis
  • Rats
  • Single-Chain Antibodies / chemistry
  • Single-Chain Antibodies / genetics
  • Single-Chain Antibodies / immunology
  • Single-Chain Antibodies / metabolism*
  • Transduction, Genetic
  • alpha-Synuclein / genetics
  • alpha-Synuclein / immunology
  • alpha-Synuclein / metabolism*


  • Apolipoproteins B
  • CHMP2B protein, mouse
  • Endosomal Sorting Complexes Required for Transport
  • Nerve Tissue Proteins
  • Single-Chain Antibodies
  • alpha-Synuclein