Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
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 January 22, 2019
Citation Information: J Clin Invest. 2019;129(4):1581-1595. https://doi.org/10.1172/JCI123931.
View: Text | PDF
Research Article Neuroscience Therapeutics

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

  • Text
  • PDF
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

×

Figure 3

ScFv antibodies mediate TDP-43 degradation.

Options: View larger image (or click on image) Download as PowerPoint
ScFv antibodies mediate TDP-43 degradation.
(A) Representative blot and ...
(A) Representative blot and quantification of TDP-43 levels in Hek293 cells transfected with pscFv9 plasmid. Graph shows quantification of TDP-43 normalized to actin and expressed as the fold change versus empty vector. n = 7–9 independent experiments (dots). One-way ANOVA P = 0.0003; *P < 0.05 and ***P < 0.0001 versus empty transfected, by Tukey’s multiple comparisons test. (B and C) Representative merged images of colocalization between scFv (Myc, green) and ubiquitin or LC3 (red). Arrows show cells with colocalization; yellow arrows indicate cells enlarged 2.5 times in the insets. Scale bars: 20 μm. The experiment was performed twice. (D) Representative blots and quantification of immunoprecipitation for all K48-polyubiquitinated (proteasome) or K63-polyubiquitinated (autophagy) proteins and Western blot for TDP-43. Graphs indicate the quantification of TDP-43 signal in immunoprecipitation experiments, expressed as the fold change versus empty vector. n = 3 independent experiment (dots). K63-ubiquitinated TDP-43: P = 0.0082, by 1-way ANOVA; **P < 0.01 versus empty vector–transfected cells, by Dunnett’s multiple comparisons test. K48-ubiquitinated TDP-43: P = 0.0128, by 1-way ANOVA; *P < 0.05 versus empty vector–transfected cells, by Dunnett’s multiple comparisons test. Data represent the mean ± SEM. Empty, no scFv (A and D); CTR, D1.3 scFv (B and C) or 8H11 anti-GFP scFv (A and D).
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts