Targeting the glycine-rich domain of TDP-43 with antibodies prevents its aggregation in vitro and reduces neurofilament levels in vivo

Acta Neuropathologica Communications

Research

Michael K. Schmidt¹  Brigitte Nuscher²  Tania F. Gendron³  Udit Sheth³  Qihui Zhou⁴  Meike Michaelsen⁴  Daniel Farny⁴  Thomas Arzberger⁵  Eszter Katona⁶  Francesca Simonetti⁷  Henrick Riemenschneider⁸  Jochen Herms⁹  Thomas Klopstock^1,10  Dieter Edbauer^1,11  Regina Feederle^1,12  Stefan Roth^1,13  Saskia Hutten^1,14  Dorothee Dormann^1,15  Lara A. Gruijs da Silva^1,16  Aloys Schepers^1,17  Andrew Flatley^1,17  Arthur Liesz^1,18 

[1] Center for Neuropathology and Prion Research, University Hospital, LMU Munich, Feodor-Lynen-Str. 23, 81377, Munich, Germany;Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität (LMU) Munich, Feodor-Lynen-Str. 17, 81377, Munich, Germany;Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, 32224, Jacksonville, FL, USA;Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, 32224, Jacksonville, FL, USA;German Center for Neurodegenerative Diseases (DZNE), Munich, Feodor-Lynen-Str. 17, 81377, Munich, Germany;German Center for Neurodegenerative Diseases (DZNE), Munich, Feodor-Lynen-Str. 17, 81377, Munich, Germany;Center for Neuropathology and Prion Research, University Hospital, LMU Munich, Feodor-Lynen-Str. 23, 81377, Munich, Germany;Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Nußbaumstr. 7, 80336, Munich, Germany;German Center for Neurodegenerative Diseases (DZNE), Munich, Feodor-Lynen-Str. 17, 81377, Munich, Germany;Ludwig-Maximilians-Universität (LMU) Munich, Graduate School of Systemic Neurosciences (GSN), 81377, Munich, Germany;German Center for Neurodegenerative Diseases (DZNE), Munich, Feodor-Lynen-Str. 17, 81377, Munich, Germany;Ludwig-Maximilians-Universität (LMU) Munich, Graduate School of Systemic Neurosciences (GSN), 81377, Munich, Germany;Institute of Molecular Physiology, Faculty of Biology, Johannes Gutenberg-Universität (JGU), Hanns-Dieter-Hüsch-Weg 17, 55128, Mainz, Germany;German Center for Neurodegenerative Diseases (DZNE), Munich, Feodor-Lynen-Str. 17, 81377, Munich, Germany;Munich Cluster of Systems Neurology (SyNergy), Feodor-Lynen-Str. 17, 81377, Munich, Germany;German Center for Neurodegenerative Diseases (DZNE), Munich, Feodor-Lynen-Str. 17, 81377, Munich, Germany;Munich Cluster of Systems Neurology (SyNergy), Feodor-Lynen-Str. 17, 81377, Munich, Germany;Center for Neuropathology and Prion Research, University Hospital, LMU Munich, Feodor-Lynen-Str. 23, 81377, Munich, Germany;German Center for Neurodegenerative Diseases (DZNE), Munich, Feodor-Lynen-Str. 17, 81377, Munich, Germany;Munich Cluster of Systems Neurology (SyNergy), Feodor-Lynen-Str. 17, 81377, Munich, Germany;Friedrich Baur Institute at the Department of Neurology, University Hospital, LMU Munich, Ziemssenstr. 1a, 80336, Munich, Germany;German Center for Neurodegenerative Diseases (DZNE), Munich, Feodor-Lynen-Str. 17, 81377, Munich, Germany;Munich Cluster of Systems Neurology (SyNergy), Feodor-Lynen-Str. 17, 81377, Munich, Germany;Ludwig-Maximilians-Universität (LMU) Munich, Graduate School of Systemic Neurosciences (GSN), 81377, Munich, Germany;German Center for Neurodegenerative Diseases (DZNE), Munich, Feodor-Lynen-Str. 17, 81377, Munich, Germany;Munich Cluster of Systems Neurology (SyNergy), Feodor-Lynen-Str. 17, 81377, Munich, Germany;Monoclonal Antibody Core Facility, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany;Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Feodor-Lynen-Str. 17, 81377, Munich, Germany;Institute of Molecular Physiology, Faculty of Biology, Johannes Gutenberg-Universität (JGU), Hanns-Dieter-Hüsch-Weg 17, 55128, Mainz, Germany;Institute of Molecular Physiology, Faculty of Biology, Johannes Gutenberg-Universität (JGU), Hanns-Dieter-Hüsch-Weg 17, 55128, Mainz, Germany;Institute of Molecular Biology (IMB), Ackermannweg 4, 55128, Mainz, Germany;Ludwig-Maximilians-Universität (LMU) Munich, Graduate School of Systemic Neurosciences (GSN), 81377, Munich, Germany;Institute of Molecular Physiology, Faculty of Biology, Johannes Gutenberg-Universität (JGU), Hanns-Dieter-Hüsch-Weg 17, 55128, Mainz, Germany;Monoclonal Antibody Core Facility, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany;Munich Cluster of Systems Neurology (SyNergy), Feodor-Lynen-Str. 17, 81377, Munich, Germany;Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Feodor-Lynen-Str. 17, 81377, Munich, Germany;

关键词: Neurodegeneration;    Amyotrophic lateral sclerosis;    Frontotemporal dementia;    TDP-43;    Immunotherapy;    Phase separation;    Aggregation;   

DOI  :  10.1186/s40478-023-01592-z

 received in 2023-03-11, accepted in 2023-05-31,  发布年份 2023

来源: Springer

【 摘 要 】

Cytoplasmic aggregation and concomitant nuclear clearance of the RNA-binding protein TDP-43 are found in ~ 90% of cases of amyotrophic lateral sclerosis and ~ 45% of patients living with frontotemporal lobar degeneration, but no disease-modifying therapy is available. Antibody therapy targeting other aggregating proteins associated with neurodegenerative disorders has shown beneficial effects in animal models and clinical trials. The most effective epitopes for safe antibody therapy targeting TDP-43 are unknown. Here, we identified safe and effective epitopes in TDP-43 for active and potential future passive immunotherapy. We prescreened 15 peptide antigens covering all regions of TDP-43 to identify the most immunogenic epitopes and to raise novel monoclonal antibodies in wild-type mice. Most peptides induced a considerable antibody response and no antigen triggered obvious side effects. Thus, we immunized mice with rapidly progressing TDP-43 proteinopathy (“rNLS8” model) with the nine most immunogenic peptides in five pools prior to TDP-43ΔNLS transgene induction. Strikingly, combined administration of two N-terminal peptides induced genetic background-specific sudden lethality in several mice and was therefore discontinued. Despite a strong antibody response, no TDP-43 peptide prevented the rapid body weight loss or reduced phospho-TDP-43 levels as well as the profound astrogliosis and microgliosis in rNLS8 mice. However, immunization with a C-terminal peptide containing the disease-associated phospho-serines 409/410 significantly lowered serum neurofilament light chain levels, indicative of reduced neuroaxonal damage. Transcriptomic profiling showed a pronounced neuroinflammatory signature (IL-1β, TNF-α, NfκB) in rNLS8 mice and suggested modest benefits of immunization targeting the glycine-rich region. Several novel monoclonal antibodies targeting the glycine-rich domain potently reduced phase separation and aggregation of TDP-43 in vitro and prevented cellular uptake of preformed aggregates. Our unbiased screen suggests that targeting the RRM2 domain and the C-terminal region of TDP-43 by active or passive immunization may be beneficial in TDP-43 proteinopathies by inhibiting cardinal processes of disease progression.Graphical Abstract

【 授权许可】

CC BY   
© The Author(s) 2023

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