Blood DDIT4 and TRIM13 Transcript Levels Mark the Early Stages of Machado-Joseph Disease.

OBJECTIVE: An abundance of select transcripts and proteins has been found to be dysregulated in blood samples of Machado-Joseph 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. METHODS: 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. RESULTS: We observed consistent dysregulation of DDIT4, TRIM13, and P2RY13 transcriptional levels in the blood of MJD patients from preclinical to symptomatic stages in Azorean and Brazilian cohorts. Combined blood DDIT4 and TRIM13 transcriptional levels show a very high accuracy to discriminate MJD carriers from matched controls (AUC ≥0.90). Levels of P2RY13 transcripts correlate with age at onset, and an abundance of DDIT4 and TRIM13 transcripts correlate with the expanded CAG repeat size in combined Azorean and Brazilian patients; and levels of TRIM13 transcripts correlate with age at onset of early-stage Azorean patients. Moreover, the abundance of TRIM13 protein is increased in the cerebral cortex of MJD patients. INTERPRETATION: Overall, blood DDIT4 and TRIM13 transcript levels are potential biomarkers of MJD. Cellular processes involving DDIT4, TRIM13, and P2RY13 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;98:107-119.