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Targeting the NAD+–PARP1–XRCC1 axis in ALS
Journal article   Peer reviewed

Targeting the NAD+–PARP1–XRCC1 axis in ALS

Md Ibrahim, Md Shahadat Hossain, Lezanne Ooi, Md Mahmudul Hasan, Shandra Ahsan, Aliasger K. Salem, Gary A. Piazza, Xiaodong Feng and Fakhrul Ahsan
Trends in molecular medicine
05/04/2026
DOI: 10.1016/j.molmed.2026.04.004
PMCID: PMC13151995
PMID: 42086408

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Abstract

•Oxidative DNA damage and impaired base excision repair/single-strand break repair increasingly emerge as contributors to motor neuron vulnerability in amyotrophic lateral sclerosis.•PARP1 hyperactivation and NAD+ depletion link persistent DNA damage signaling to metabolic stress in amyotrophic lateral sclerosis models and patient-derived systems.•The NAD+–PARP1–XRCC1 axis provides a mechanistic framework connecting defective DNA repair with bioenergetic failure in amyotrophic lateral sclerosis.•Catalytic PARP1 inhibition and NAD+ restoration represent complementary, mechanism-based therapeutic strategies that warrant further preclinical and clinical evaluation.•Proximity-labeling proteomics and RNA-based delivery platforms may enable the identification and restoration of defective DNA repair modules in vulnerable neurons. Amyotrophic lateral sclerosis (ALS) remains a fatal neurodegenerative disease with few effective therapies. Emerging evidence indicates that oxidative DNA damage, defective base excision and single-strand break repair, and progressive NAD+ depletion contribute to motor neuron degeneration. The NAD+–PARP1–XRCC1 axis sits at the intersection of genome maintenance and metabolic control, linking DNA damage signaling to cellular bioenergetics. When dysregulated, this pathway may drive persistent PARP1 activation, failed repair, and energetic collapse. In this review, we integrate mechanistic and translational evidence supporting this axis as a therapeutic target in ALS. We propose a staged translational framework that prioritizes repurposable low-trapping PARP1 inhibitors combined with NAD+ support, followed by central nervous system-directed RNA-lipid nanoparticle delivery of repair factors, with poly(ADP-ribose) and NAD+ metabolites as pharmacodynamic biomarkers. Amyotrophic lateral sclerosis (ALS) remains a fatal neurodegenerative disease with few effective therapies. Emerging evidence indicates that oxidative DNA damage, defective base excision and single-strand break repair, and progressive NAD+ depletion contribute to motor neuron degeneration. The NAD+–PARP1–XRCC1 axis sits at the intersection of genome maintenance and metabolic control, linking DNA damage signaling to cellular bioenergetics. When dysregulated, this pathway may drive persistent PARP1 activation, failed repair, and energetic collapse. In this review, we integrate mechanistic and translational evidence supporting this axis as a therapeutic target in ALS. We propose a staged translational framework that prioritizes repurposable low-trapping PARP1 inhibitors combined with NAD+ support, followed by central nervous system-directed RNA-lipid nanoparticle delivery of repair factors, with poly(ADP-ribose) and NAD+ metabolites as pharmacodynamic biomarkers.
 Amyotrophic Lateral Sclerosis DNA damage repair NAD+ metabolism neuroprotection PARP1 hyperactivation XRCC1 dysfunction

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