{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T13:57:29Z","timestamp":1756994249290,"version":"3.41.0"},"reference-count":74,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T00:00:00Z","timestamp":1741132800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>An abundance of select transcripts and proteins has been found to be dysregulated in blood samples of Machado\u2013Joseph disease (MJD) carriers. Here, we aimed to: (1) identify blood transcriptional changes as potential biomarkers of MJD; (2) correlate levels of differentially expressed blood transcripts with MJD carriers features; and (3) evaluate whether the identified differential abundance of blood transcripts in MJD patients is preserved in MJD brains.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used unbiased RNA microarray and quantitative polymerase chain reaction to assess transcript levels in blood and brain samples, and western blot analysis to evaluate the abundance of specific proteins in brain samples.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We observed consistent dysregulation of <jats:italic>DDIT4<\/jats:italic>, <jats:italic>TRIM13<\/jats:italic>, and <jats:italic>P2RY13<\/jats:italic> transcriptional levels in the blood of MJD patients from preclinical to symptomatic stages in Azorean and Brazilian cohorts. Combined blood <jats:italic>DDIT4<\/jats:italic> and <jats:italic>TRIM13<\/jats:italic> transcriptional levels show a very high accuracy to discriminate MJD carriers from matched controls (AUC \u22650.90). Levels of <jats:italic>P2RY13<\/jats:italic> transcripts correlate with age at onset, and an abundance of <jats:italic>DDIT4<\/jats:italic> and <jats:italic>TRIM13<\/jats:italic> transcripts correlate with the expanded CAG repeat size in combined Azorean and Brazilian patients; and levels of <jats:italic>TRIM13<\/jats:italic> transcripts correlate with age at onset of early\u2010stage Azorean patients. Moreover, the abundance of TRIM13 protein is increased in the cerebral cortex of MJD patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Overall, blood <jats:italic>DDIT4<\/jats:italic> and <jats:italic>TRIM13<\/jats:italic> transcript levels are potential biomarkers of MJD. Cellular processes involving <jats:italic>DDIT4<\/jats:italic>, <jats:italic>TRIM13<\/jats:italic>, and <jats:italic>P2RY13<\/jats:italic> appear to be commonly dysregulated in the blood and brain of MJD patients, indicating the involvement of these genes in MJD pathogenesis. ANN NEUROL 2025;98:107\u2013119<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.27222","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T15:35:27Z","timestamp":1741707327000},"page":"107-119","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Blood <scp><i>DDIT4<\/i><\/scp> and <scp><i>TRIM13<\/i><\/scp> Transcript Levels Mark the Early Stages of Machado\u2013Joseph Disease"],"prefix":"10.1002","volume":"98","author":[{"given":"Ana F.","family":"Ferreira","sequence":"first","affiliation":[{"name":"Faculdade de Ci\u00eancias e Tecnologia Universidade dos A\u00e7ores  Ponta Delgada Portugal"},{"name":"UMIB\u2010Unit for Multidisciplinary Research in Biomedicine, ICBAS\u2010School of Medicine and Biomedical Sciences University of Porto  Porto 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