2026-07-03 アリゾナ大学
Microscopic image of lab-grown human motor neurons carrying an ALS mutation, the type of cell the disease destroys. Green identifies motor neurons, purple highlights the neurons and their branching fibers and blue marks the cell nuclei. Dr. Ju Gao
＜関連情報＞
- https://news.arizona.edu/news/can-fatal-nerve-disease-be-slowed-u-study-finds-promising-new-approach
- https://www.nature.com/articles/s43587-026-01166-3
TDP-43の低複雑性ドメイン内の保存領域を治療標的とすることは、神経保護作用があり、筋萎縮性側索硬化症マウスの生存期間を延長する Therapeutic targeting of the conserved region within the low-complexity domain of TDP-43 is neuroprotective and extends survival in amyotrophic lateral sclerosis mice
Ju Gao,Devanshi Shukla,Mao Ding,Siyue Qin,Fan Tang,Evelyn Guerrero,Lauren Vicuna,Jiawei Xu,Hongling Li,Masaru Miyagi,Pan P. Li,Jingjing Liang & Xinglong Wang
Nature Aging Published:03 July 2026
DOI:https://doi.org/10.1038/s43587-026-01166-3
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.
