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

## TL;DR

Researchers developed a new tool that targets a misbehaving protein linked to neurological diseases and showed it can reduce harmful effects in lab cells.

## Contribution

A novel scFv intrabody (D7) was identified that targets wildtype TDP-43 and reduces disease-related protein accumulation and metabolic changes.

## Key findings

- The scFv D7 intrabody promotes proteasomal degradation of the 35-kDa C-terminal TDP-43 fragment.
- D7 reversed TDP-43-induced lipid metabolism alterations in a cellular model.
- A 3D structure of full-length wt TDP-43 was generated and used for epitope mapping.

## Abstract

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.