Monoclonal full-length antibody against TAR DNA binding protein 43 reduces related proteinopathy in neurons
Silvia Pozzi, Philippe Codron, Geneviève Soucy, Laurence Renaud, Pierre Junior Cordeau, Kallol Dutta, Christine Bareil, Jean-Pierre Julien
Silvia Pozzi, Philippe Codron, Geneviève Soucy, Laurence Renaud, Pierre Junior Cordeau, Kallol Dutta, Christine Bareil, Jean-Pierre Julien
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Research Article Neuroscience Therapeutics

Monoclonal full-length antibody against TAR DNA binding protein 43 reduces related proteinopathy in neurons

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), 2 incurable neurodegenerative disorders, share the same pathological hallmark named TDP43 (TAR DNA binding protein 43) proteinopathy. This event is characterized by a consistent cytoplasmic mislocalization and aggregation of the protein TDP43, which loses its physiological properties, leading neurons to death. Antibody-based approaches are now emerging interventions in the field of neurodegenerative disorders. Here, we tested the target specificity, in vivo distribution, and therapeutic efficacy of a monoclonal full-length antibody, named E6, in TDP43-related conditions. We observed that the antibody recognizes specifically the cytoplasmic fraction of TDP43. We demonstrated its ability in targeting large neurons in the spinal cord of mice and in reducing TDP43 mislocalization and NF-κB activation. We also recognized the proteasome as well as the lysosome machineries as possible mechanisms used by the antibody to reduce TDP43 proteinopathy. To our knowledge, this is the first report showing the therapeutic efficacy and feasibility of a full-length antibody against TDP43 in reducing TDP43 proteinopathy in spinal neurons of an ALS/FTLD mouse model.

Authors

Silvia Pozzi, Philippe Codron, Geneviève Soucy, Laurence Renaud, Pierre Junior Cordeau, Kallol Dutta, Christine Bareil, Jean-Pierre Julien

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Figure 8

Treatment with E6 antibody reduces cytoplasmic TDP43 and nuclear p65 in lumbar motor neurons.

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Treatment with E6 antibody reduces cytoplasmic TDP43 and nuclear p65 in ...
(A) Representative high-magnification colorimetric heatmap images of TDP43 immunofluorescence. Single channels images are shown in Supplemental Figure 8C. Scale bar: 10 μm. Arrowheads show cytoplasmic TDP43. (B) Graph represents quantification of nuclear to cytoplasmic integrated density of TDP43 signal in single large neurons counted in ventral horns of mice lumbar spinal cord. Data are represented as mean ± SEM; number of counted neurons (dots) from 4 independent mice (numbered 1–4) is shown in the graph; 1-way ANOVA (F11,934 = 36.98, P < 0.0001), ***P < 0.0001 by Tukey’s multiple comparison test. (C) Representative high-magnification colorimetric heatmap images of p65 immunofluorescence. Single channels images are shown in Supplemental Figure 9A. Scale bar: 10 μm. (D) Graph represents quantification of nuclear integrated density of p65 signal in single neurons counted in anterior horn of the lumbar spinal cord. Data are represented as mean ± SEM; number of counted neurons (dots) from 4 independent mice (numbered 1–4) is shown in the graph; 1-way ANOVA (F11,667 = 36.39, P = 0.0011), ***P < 0.001 by Tukey’s multiple comparison test. (E) Representative images of immunofluorescence for microglial cells (CD11b, red) merged with nuclei (Hoechst, blue) performed on lumbar spinal cord of treated mice. Scale bar: 20 μm. (F) Graphs represent quantification of percentage of area covered by CD11b signal (area fraction). Data are represented as mean ± SEM; n = 4 independent mice, dots. One-way ANOVA (F2,9 = 6.906, P = 0.0151),*P < 0.05 by Tukey’s multiple comparison test. The control antibody used was clone 807.33.