Therapeutic targeting of the conserved region within the low-complexity domain of TDP-43 is neuroprotective and extends survival in amyotrophic lateral sclerosis mice

  • Nat Aging. 2026 Jul 3. doi: 10.1038/s43587-026-01166-3.
Ju Gao  #  1 ,  Devanshi Shukla  #  1 ,  Mao Ding  1 ,  Siyue Qin  1 ,  Fan Tang  2 ,  Evelyn Guerrero  1 ,  Lauren Vicuna  1 ,  Jiawei Xu  1 ,  Hongling Li  1 ,  Masaru Miyagi  3 ,  Pan P Li  2 ,  Jingjing Liang  4 ,  Xinglong Wang  5
Affiliations
  • 1. Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA.
  • 2. Department of Psychiatry and Behavioral Sciences, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 3. Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA.
  • 4. Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, Tucson, AZ, USA.
  • 5. Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA. [email protected].
  • # Contributed equally.
PMID: 42399370 DOI: 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.

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