Adenosine Deaminase-Mediated Purine Dysfunction Leads to DNA Repair Inhibition and Senescence in Sporadic Amyotrophic Lateral Sclerosis

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Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by the death of motor neurons leading to paralysis and death generally 3–5 years post-symptom onset. ALS is a cell- and non-cell-autonomous disease, with glia such as astrocytes influencing disease pathology and progression. Our laboratory has previously identified purine metabolism dysfunction in induced neural progenitor cell-derived astrocytes (iAstrocytes) from sporadic ALS (SALS) cases, driven by loss of the enzyme adenosine deaminase (ADA). Here, we have demonstrated that loss of ADA, along with changes to ecto-5′-nucleotidase and hypoxanthine-guanine phosphoribosyl transferase led to disruption in purine metabolite levels, linked to the level of the ADA enzyme. These alterations were recapitulated in SALS CSF and post-mortem tissue, with ageing and sex affecting purine metabolite levels downstream of ADA and positively correlating with disease progression. Loss of ADA led to reduced 53BP1-mediated DNA repair and increased P16 levels, which was recapitulated in control iAstrocytes via ADA inhibition. Our findings indicate that TDP43 dysfunction drives impairment of ADA-mediated purine metabolism in vitro, leading to downstream effects that include DNA damage, likely through inhibition of DNA repair mechanisms, and the induction of cellular senescence. Furthermore, these results suggest that therapeutic targeting of the ADA pathway may help slow ALS disease progression.
Funding Information
  • University of Sheffield (SBF005\1064)
  • University of Sheffield, Faculty of Health PhD Studentship (Allen/Jun23/964-793)
  • University of Sheffield, Faculty of Health PhD Studentship (Allen 887-791)
  • University of Sheffield, Faculty of Health PhD Studentship (West/Oct22/909-792)
  • UK Foreign, Commonwealth and Development Office
  • NIHR Sheffield Biomedical Research Centre (BRC-203321)
  • NIHR Sheffield Biomedical Research Centre (NF-SI-0617-10077)
  • MNDA ‘A Multicentre Biomarker Resource Strategy’ in ALS (AMBRoSIA PJS 972-797)
  • Barncancerfonden (TJ2022-0063)
  • Swedish Cancer Society (23-2782-Pj)
  • Swedish Cancer Society (26-5197-IA-SIA)
  • Medical Research Council Canada (MR/W00416X/1)

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