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

Hall, Benjamin; Ebrahim, Yasmina M.; Sharpe, Joanne L.; Makhija, Sangeet; Ellis, Brittany C. S.; Wong, Kari E.; Walker, Heather; Yagüe-Capilla, Miriam; Timmons, Hannah O.; Bradley, Arian; Nightingale, Ella; Ross, Rees; Allen, Chloe F.; Gatto, Noemi; Garland, Herbie; Soni, Nikita; Kolb, Stephen J.; Highley, J. Robin; Hautbergue, Guillaume M.; Rudd, Sean G.; West, Ryan J. H.; Shaw, Pamela J.; Allen, Scott P.

doi:10.3390/ijms27188236

Open AccessArticle

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

by

Benjamin Hall

¹,

Yasmina M. Ebrahim

¹

,

Joanne L. Sharpe

¹

,

Sangeet Makhija

¹,

Brittany C. S. Ellis

¹,

Kari E. Wong

²,

Heather Walker

³

,

Miriam Yagüe-Capilla

^4,5,6,

Hannah O. Timmons

¹

,

Arian Bradley

¹,

Ella Nightingale

¹,

Rees Ross

¹,

Chloe F. Allen

¹,

Noemi Gatto

¹,

Herbie Garland

¹,

Nikita Soni

¹

,

Stephen J. Kolb

^7,8,

J. Robin Highley

¹,

Guillaume M. Hautbergue

¹

,

Sean G. Rudd

⁴

,

Ryan J. H. West

¹

,

Pamela J. Shaw

¹

and

Scott P. Allen

^1,*

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¹

Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK

²

Metabolon Inc., Morrisville, NC 27560, USA

³

biOMICS Mass Spectrometry Facility, University of Sheffield, Alfred Denny Building, Western Bank, Sheffield S10 2TN, UK

⁴

SciLifeLab, Department of Oncology-Pathology, Karolinska Institute, 41012 Stockholm, Sweden

⁵

Instituto de Biomedicina de Sevilla (IBiS), Avda Manuel Siurot S/N, 41013 Seville, Spain

⁶

Departamento de Biologia Celular, Facultad de Biologia, Universidad de Sevilla, Avenida Reina Mercedes 6, 41012 Seville, Spain

⁷

Department of Neurology, The Ohio State University Wexner Medical Center, 410 W. 10th Avenue, Columbus, OH 43210, USA

⁸

Department of Biological Chemistry & Pharmacology, The Ohio State University Wexner Medical Center, 370 W. 9th Avenue, Columbus, OH 43210, USA

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2026, 27(18), 8236; https://doi.org/10.3390/ijms27188236

Submission received: 14 August 2026 / Revised: 10 September 2026 / Accepted: 11 September 2026 / Published: 16 September 2026

(This article belongs to the Special Issue Purine Signaling as a Therapeutic Target in Human Diseases)

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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.

Keywords: ADA; ALS; astrocyte; metabolomics; MND; purine metabolism

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MDPI and ACS Style

Hall, B.; Ebrahim, Y.M.; Sharpe, J.L.; Makhija, S.; Ellis, B.C.S.; Wong, K.E.; Walker, H.; Yagüe-Capilla, M.; Timmons, H.O.; Bradley, A.; et al. Adenosine Deaminase-Mediated Purine Dysfunction Leads to DNA Repair Inhibition and Senescence in Sporadic Amyotrophic Lateral Sclerosis. Int. J. Mol. Sci. 2026, 27, 8236. https://doi.org/10.3390/ijms27188236

AMA Style

Hall B, Ebrahim YM, Sharpe JL, Makhija S, Ellis BCS, Wong KE, Walker H, Yagüe-Capilla M, Timmons HO, Bradley A, et al. Adenosine Deaminase-Mediated Purine Dysfunction Leads to DNA Repair Inhibition and Senescence in Sporadic Amyotrophic Lateral Sclerosis. International Journal of Molecular Sciences. 2026; 27(18):8236. https://doi.org/10.3390/ijms27188236

Chicago/Turabian Style

Hall, Benjamin, Yasmina M. Ebrahim, Joanne L. Sharpe, Sangeet Makhija, Brittany C. S. Ellis, Kari E. Wong, Heather Walker, Miriam Yagüe-Capilla, Hannah O. Timmons, Arian Bradley, and et al. 2026. "Adenosine Deaminase-Mediated Purine Dysfunction Leads to DNA Repair Inhibition and Senescence in Sporadic Amyotrophic Lateral Sclerosis" International Journal of Molecular Sciences 27, no. 18: 8236. https://doi.org/10.3390/ijms27188236

APA Style

Hall, B., Ebrahim, Y. M., Sharpe, J. L., Makhija, S., Ellis, B. C. S., Wong, K. E., Walker, H., Yagüe-Capilla, M., Timmons, H. O., Bradley, A., Nightingale, E., Ross, R., Allen, C. F., Gatto, N., Garland, H., Soni, N., Kolb, S. J., Highley, J. R., Hautbergue, G. M., ... Allen, S. P. (2026). Adenosine Deaminase-Mediated Purine Dysfunction Leads to DNA Repair Inhibition and Senescence in Sporadic Amyotrophic Lateral Sclerosis. International Journal of Molecular Sciences, 27(18), 8236. https://doi.org/10.3390/ijms27188236

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

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