title: ESCRT-mediated uptake and degradation of brain-targeted α-synuclein single chain antibody attenuates neuronal degeneration in vivo.
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.
authors.affiliation: NeuroTransit, Inc., San Diego, California, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Spencer
authors.affiliation: Department of Chemical Engineering, Arizona State University, Tempe, Arizona, USA.
authors.forename: Sharareh
authors.initials: S
authors.lastname: Emadi
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Desplats
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Simona
authors.initials: S
authors.lastname: Eleuteri
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Michael
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Kori
authors.initials: K
authors.lastname: Kosberg
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Patrick
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Tania
authors.initials: T
authors.lastname: Gonzalez
authors.affiliation: Department of Chemical Engineering, Arizona State University, Tempe, Arizona, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Sierks
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA; Department of Pathology, University of California, San Diego, La Jolla, California, USA. Electronic address: emasliah@ucalsd.edu.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001055:Apolipoproteins B / Q000737:chemistry / Q000378:metabolism; D001343:Autophagy; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D023061:Gene Order; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D021381:Protein Transport; D059748:Proteolysis; D051381:Rats; D057127:Single-Chain Antibodies / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014161:Transduction, Genetic; D051844:alpha-Synuclein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D001055:Apolipoproteins B; C525139:CHMP2B protein, mouse; D056827:Endosomal Sorting Complexes Required for Transport; D009419:Nerve Tissue Proteins; D057127:Single-Chain Antibodies; D051844:alpha-Synuclein