Loss of adenosine deaminase impairs DNA repair and triggers astrocyte senescence in ALS

In human cell models, cerebrospinal fluid, and post-mortem tissue from patients with sporadic amyotrophic lateral sclerosis, researchers investigated how purine metabolism dysfunction drives disease pathology. The team evaluated patient-derived astrocytes alongside fluid and tissue samples. They found that loss of the enzyme adenosine deaminase, together with altered purine enzyme activity, disrupted purine metabolite levels. Downstream purine changes correlated with age, sex, and disease progression in patient samples. In cultured astrocytes, TDP43 dysfunction impaired adenosine deaminase-driven purine metabolism. This loss suppressed 53BP1-mediated DNA repair and increased levels of the senescence marker P16. Pharmacological inhibition of adenosine deaminase in control astrocytes reproduced this DNA repair impairment and elevated P16 levels.