scFv intrabody targeting wildtype TDP-43 presents protective effects in a cellular model of TDP-43 proteinopathy
TDP-43 proteinopathies are neurological disorders marked by the abnormal accumulation of TDP-43 in the cytoplasm. This mislocalization disrupts the normal function of the protein. In most cases, it is the wildtype (wt) form of the protein that is involved. An untargeted high-throughput screen of a single-chain variable fragment (scFv) library was performed using phage display against human full-length wt TDP-43. Two scFvs (B1 and D7) were retained following cellular expression (then termed intrabodies) and colocalization with cytoplasmic TDP-43 in vitro. We generated a 3D structure of full length wt TDP-43 in silico, and used it for epitope mapping. In a cellular model of TDP-43 proteinopathy, D7 enhanced the proteasomal degradation of the insoluble 35-kDa C-terminal fragment of TDP-43 and reversed some TDP-43-induced metabolomic alterations, particularly relating to the lipid metabolism. Our findings offer a new scFv intrabody that bind to human wtTDP-43 and modify cellular pathways associated with TDP-43 proteinopathies.
Authors
- Philippe Corcia (ORCID: https://orcid.org/0000-0002-1625-8845)
- Shanez Haouari
- Olivier Hérault (ORCID: https://orcid.org/0000-0002-7419-1124)
- Yara Al Ojaimi (ORCID: https://orcid.org/0000-0002-5270-155X)
- Anna A. Chami
- Samira Osman (ORCID: https://orcid.org/0009-0002-0105-621X)
- Antoine Lefèvre (ORCID: https://orcid.org/0009-0003-9032-1085)
- Débora Lanznaster (ORCID: https://orcid.org/0000-0001-5911-3120)
- Hélène Blasco (ORCID: https://orcid.org/0000-0001-6107-0035)
- Patrick Emond (ORCID: https://orcid.org/0000-0002-5324-2164)
- Hugo Alarcan (ORCID: https://orcid.org/0000-0001-8707-1722)
- Christian Andrés (ORCID: https://orcid.org/0000-0002-5062-3156)
- Pierre Martineau (ORCID: https://orcid.org/0000-0002-7993-7183)
- Patrick Vourc’h (ORCID: https://orcid.org/0000-0001-7960-8139)
- Rudolf Hergesheimer (ORCID: https://orcid.org/0000-0002-9056-5122)
- Audrey Dangoumau (ORCID: https://orcid.org/0000-0002-5038-1839)
- Jérôme Bourgeais (ORCID: https://orcid.org/0000-0002-2557-9624)
- Johanna Augros
Institutions
- Université de Tours (FR)
- Inserm (FR)
- Université de Montpellier (FR)
- Centre Hospitalier Universitaire de Tours (FR)
- Institut de Recherche en Cancérologie de Montpellier (FR)
Publication Details
- Journal
- PLoS ONE
- Published
- 2025-08-04
- DOI
- https://doi.org/10.1371/journal.pone.0322021
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres Maladies du Motoneurone
- Conseil Régional du Centre-Val de Loire