Therapeutic targeting of the conserved region within the low-complexity domain of TDP-43 is neuroprotective and extends survival in amyotrophic lateral sclerosis mice.
Overview
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona,Tucson, AZ USA
- Department of Psychiatry and Behavioral Sciences, Division of Neurobiology, Johns Hopkins University School of Medicine,Baltimore, MD USA
- Department of Pharmacology, Case Western Reserve University,Cleveland, OH USA
- Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona,Tucson, AZ USA
Abstract
Autosomal dominant mutations in TARDBP, encoding TAR DNA-binding protein 43 (TDP-43), cause amyotrophic lateral sclerosis (ALS), and TDP-43 pathology is a hallmark of multiple aging-associated neurodegenerative diseases. Despite its pathological role, effective therapies remain limited by the lack of safe, potent molecules targeting TDP-43 neurotoxicity. Here we show that the conserved α-helical region spanning residues 320–340 (conserved region or CR) is a therapeutically actionable target for TDP-43 neurotoxicity. Deletion of CR markedly suppressed TDP-43-induced neuronal death. Structure-based virtual screening identified XL20, a brain-penetrant small molecule that engages CR and confers neuroprotection without affecting TDP-43 splicing activity. XL20 alleviated motor neuron loss, extended survival in TDP-43 p.Ala315Thr ALS mice and enhanced neuronal function in p.Gln331Lys induced pluripotent stem cell-derived human ALS motor neurons. Mechanistically, targeting CR suppressed TDP-43 mitochondrial localization and restored mitochondrial function, likely through liquid–liquid phase separation. Our findings highlight CR as a therapeutic target for TDP-43-associated neurodegeneration and support CR-binding small molecules as therapeutic candidates.
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
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Data
Datasets cited
- bioproject:PRJNA1220042, at NCBI BioProject; found in “Data availability”
- pride:PXD060626, at PRIDE; found in “Data availability”
Data availability
The mass spectrometry proteomics data generated in this study have been deposited in the ProteomeXchange Consortium via the PRIDE partner repository under accession code PXD060626 (http://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 2, 28 September 2026
- Publisher: n/a → Nature Portfolio
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 13 authors, 3 keywords, 11 MeSH terms, 3 funders, 69 references.
Cite
This paper
Gao, J., Shukla, D., Ding, M., Qin, S., Tang, F., Guerrero, E., Vicuna, L., Xu, J., Li, H., Miyagi, M., Li, P. P., Liang, J., & Wang, X. (2026). Therapeutic targeting of the conserved region within the low-complexity domain of TDP-43 is neuroprotective and extends survival in amyotrophic lateral sclerosis mice. Nature aging, 6(8), 1667-1683. https://
BibTeX
@article{gao2026therapeu
author = {Gao, Ju and Shukla, Devanshi and Ding, Mao and Qin, Siyue and Tang, Fan and Guerrero, Evelyn and Vicuna, Lauren and Xu, Jiawei and Li, Hongling and Miyagi, Masaru and Li, Pan P. and Liang, Jingjing and Wang, Xinglong},
title = {{Therapeutic targeting of the conserved region within the low-complexity domain of TDP-43 is neuroprotective and extends survival in amyotrophic lateral sclerosis mice}},
journal = {Nature aging},
year = {2026},
month = jul,
volume = {6},
number = {8},
pages = {1667--1683},
publisher = {Nature Portfolio},
issn = {2662-8465},
doi = {10.1038/
url = {https://
pmid = {42399370},
pmcid = {PMC13472882}
}
RIS
TY - JOUR
AU - Gao, Ju
AU - Shukla, Devanshi
AU - Ding, Mao
AU - Qin, Siyue
AU - Tang, Fan
AU - Guerrero, Evelyn
AU - Vicuna, Lauren
AU - Xu, Jiawei
AU - Li, Hongling
AU - Miyagi, Masaru
AU - Li, Pan P.
AU - Liang, Jingjing
AU - Wang, Xinglong
TI - Therapeutic targeting of the conserved region within the low-complexity domain of TDP-43 is neuroprotective and extends survival in amyotrophic lateral sclerosis mice
T2 - Nature aging
J2 - Nat Aging
PY - 2026
DA - 2026/
VL - 6
IS - 8
SP - 1667
EP - 1683
SN - 2662-8465
PB - Nature Portfolio
DO - 10.1038/
UR - https://
LA - en
ER -
CSL-JSON
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