scFv intrabody targeting wildtype TDP-43 presents protective effects in a cellular model of TDP-43 proteinopathy.

scFv intrabody targeting wildtype TDP-43 presents protective effects in a cellular model of TDP-43 proteinopathy.

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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 s...

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Main Authors: Yara Al Ojaimi, Rudolf Hergesheimer, Anna A Chami, Hugo Alarcan, Johanna Augros, Audrey Dangoumau, Shanez Haouari, Jérôme Bourgeais, Antoine Lefevre, Samira Osman, Patrick Emond, Patrick Vourc'h, Christian R Andres, Philippe Corcia, Olivier Herault, Pierre Martineau, Débora Lanznaster, Hélène Blasco
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2025-01-01
Series:PLoS ONE
Online Access:https://doi.org/10.1371/journal.pone.0322021
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Summary: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.
ISSN:1932-6203

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