Virus-mediated delivery of antibody targeting TAR DNA-binding protein-43 mitigates associated neuropathology
Silvia Pozzi, … , Claude Gravel, Jean-Pierre Julien
Silvia Pozzi, … , Claude Gravel, Jean-Pierre Julien
Published April 1, 2019; First published January 22, 2019
Citation Information: J Clin Invest. 2019;129(4):1581-1595. https://doi.org/10.1172/JCI123931.
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Research Article Neuroscience Therapeutics

Virus-mediated delivery of antibody targeting TAR DNA-binding protein-43 mitigates associated neuropathology

Abstract

The cytoplasmic aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of degenerating neurons in amyotrophic lateral sclerosis (ALS) and subsets of frontotemporal dementia (FTD). In order to reduce TDP-43 pathology, we generated single-chain (scFv) antibodies against the RNA recognition motif 1 (RRM1) of TDP-43, which is involved in abnormal protein self-aggregation and interaction with p65 NF-κB. Virus-mediated delivery into the nervous system of a scFv antibody, named VH7Vk9, reduced microgliosis in a mouse model of acute neuroinflammation and mitigated cognitive impairment, motor defects, TDP-43 proteinopathy, and neuroinflammation in transgenic mice expressing ALS-linked TDP-43 mutations. These results suggest that antibodies targeting the RRM1 domain of TDP-43 might provide new therapeutic avenues for the treatment of ALS and FTD.

Authors

Silvia Pozzi, Sai Sampath Thammisetty, Philippe Codron, Reza Rahimian, Karine Valérie Plourde, Geneviève Soucy, Christine Bareil, Daniel Phaneuf, Jasna Kriz, Claude Gravel, Jean-Pierre Julien

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Figure 4

ScFv antibodies reduce TDP-43 mislocalization and aggregation.

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ScFv antibodies reduce TDP-43 mislocalization and aggregation. (A) Repre...
(A) Representative enlarged images and TDP-43 mislocalization determined by quantification of the integrated density of TDP-43 immunoreactivity in nuclear and cytoplasmic compartments. Images show merged scFv (Myc, green), hTDP-43 (red), and Hoechst (nuclei, blue) channels, and lines circumscribe the perimeter of the representative cells. Scale bars: 5 μm. Data in the graph represent the cytoplasmic to nuclear ratio quantified in at least 200 cells per frame. n = 5–10 different frames (dots) analyzed from 2 independent experiments. One-way ANOVA P < 0.0001; ***P < 0.001 versus control-transfected cells; #P < 0.05 and ###P < 0.001 versus empty vector–transfected cells, by Tukey’s multiple comparisons test. (B) Representative image and quantification of dot blot analysis for soluble or insoluble TDP-43 in transfected Hek293 cells treated with 50 μM EA. Data represent TDP-43 immunoreactivity normalized to Ponceau from 5 to 9 replicates (dots) from 3 independent experiments. Two-way ANOVA interaction P = 0.249, scFv P = 0.0014, and soluble/insoluble P < 0.0001; ***P < 0.001 versus empty vector–transfected cells, by Tukey’s multiple comparisons test. Data represent the mean ± SEM. Empty, no scFv, CTR, control D1.3 scFv.