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The most frequent genetic cause of ALS is a hexanucleotide repeat expansion (HRE) in the chromosome 9 open reading frame 72 (C9orf72) gene, that has three major hypothesised pathological mechanisms including the production of dipeptide repeat proteins (DPRs). Our laboratory has previously identified purine metabolism dysfunction in induced neural progenitor cell-derived astrocytes (iAstrocytes) from C9orf72 ALS (C9-ALS) cases (C9-iAstrocytes), driven by loss of the enzyme adenosine deaminase (ADA). Here, we have demonstrated that loss of ADA along with changes to ecto-5\u2032-nucleotidase and hypoxanthine-guanine phosphoribosyl transferase led to disruption in purine metabolite levels including purine dNTP output. These changes were recapitulated in patient CSF, whilst loss of ADA was recapitulated in patient white matter. Immunofluorescence also demonstrated purinosome formation dysfunction in C9-iAstrocytes. These changes are likely driven by DPRs as ADA loss was recapitulated in in vitro and in vivo DPR models. Finally, ADA levels could be recovered by reducing DPR levels either by inhibiting serine\/arginine-rich splicing factor 1 or overexpressing RuvB-like 2. Our data demonstrate that DPR production negatively affects purine function in C9-ALS suggesting a potentially pivotal role for purine metabolism dysfunction in C9-ALS pathology.<\/jats:p>","DOI":"10.3390\/ijms27041953","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T15:28:18Z","timestamp":1771428498000},"page":"1953","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Antisense Dipeptide Repeat Proteins Drive Widescale Purine Metabolism Aberration in C9orf72 Amyotrophic Lateral Sclerosis via ADA"],"prefix":"10.3390","volume":"27","author":[{"given":"Benjamin","family":"Hall","sequence":"first","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydia","family":"Castelli","sequence":"additional","affiliation":[{"name":"Sheffield Institute for 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Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"12408","DOI":"10.1038\/ncomms12408","article-title":"Projected increase in amyotrophic lateral sclerosis from 2015 to 2040","volume":"7","author":"Arthur","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1080\/21678421.2024.2447919","article-title":"Amyotrophic lateral sclerosis estimated prevalence cases from 2022 to 2030, data from the national ALS Registry","volume":"26","author":"Mehta","year":"2025","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1016\/S0140-6736(17)32154-2","article-title":"Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990\u20132016: A systematic analysis for the Global Burden of Disease Study 2016","volume":"390","author":"Vos","year":"2017","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.neuron.2011.09.011","article-title":"Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS","volume":"72","author":"Mackenzie","year":"2011","journal-title":"Neuron"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.neuron.2011.09.010","article-title":"A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD","volume":"72","author":"Renton","year":"2011","journal-title":"Neuron"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/S1474-4422(12)70043-1","article-title":"Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: A cross-sectional study","volume":"11","author":"Majounie","year":"2012","journal-title":"Lancet Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.3389\/fnins.2019.01310","article-title":"ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now?","volume":"13","author":"Mejzini","year":"2019","journal-title":"Front. 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