Proteasome-targeted nanobodies alleviate pathology and functional decline in an α-synuclein-based Parkinson's disease model

NPJ Parkinson's Disease
Diptaman ChatterjeeJeffrey H Kordower

Abstract

Therapeutics designed to target α-synuclein (α-syn) aggregation may be critical in halting the progression of pathology in Parkinson's disease (PD) patients. Nanobodies are single-domain antibody fragments that bind with antibody specificity, but allow readier genetic engineering and delivery. When expressed intracellularly as intrabodies, anti-α-syn nanobodies fused to a proteasome-targeting proline, aspartate or glutamate, serine, and threonine (PEST) motif can modulate monomeric concentrations of target proteins. Here we aimed to validate and compare the in vivo therapeutic potential of gene therapy delivery of two proteasome-directed nanobodies selectively targeting α-syn in a synuclein overexpression-based PD model: VH14*PEST (non-amyloid component region) and NbSyn87*PEST (C-terminal region). Stereotaxic injections of adeno-associated viral 5-α-syn (AAV5-α-syn) into the substantia nigra (SN) were performed in Sprague-Dawley rats that were sorted into three cohorts based on pre-operative behavioral testing. Rats were treated with unilateral SN injections of vectors for VH14*PEST, NbSyn87*PEST, or injected with saline 3 weeks post lesion. Post-mortem assessments of the SN showed that both nanobodies markedly reduced the lev...Continue Reading

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Citations

Mar 17, 2019·International Journal of Molecular Sciences·Anne H S MartinelliRodrigo Ligabue-Braun
Mar 7, 2020·Biomolecules·Margaux TeilBenjamin Dehay
Jun 3, 2020·Nature Communications·Christoph GerdesFelipe Opazo
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Mar 17, 2020·Journal of Parkinson's Disease·Yun-Hsiang ChenYun Wang
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Nov 16, 2019·NPJ Parkinson's Disease·Bryan A KillingerJeffrey H Kordower
Apr 18, 2020·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Congcong ZhangAndrea L J Marschall
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Oct 27, 2020·Journal of Parkinson's Disease·Anne-Marie CastonguayMartin Lévesque
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May 6, 2019·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Zhipeng WangHui Yang

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Methods Mentioned

BETA
surface display
phage display

Software Mentioned

Scion Image
GraphPad Prism
Fluoview

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