Small RNA sequencing identifies serum tDR-1:34-Gly-GCC tiRNA levels as a biomarker for survival in amyotrophic lateral sclerosis

Survival is highly variable in amyotrophic lateral sclerosis (ALS), complicating prognosis and clinical trial design. Despite advances in biomarker development, accessible prognostic tools are limited. Small non-coding (snc) RNAs are a recently discovered biomarker class showing differential regulation across neurodegenerative diseases, including ALS. Here, we explored changes in sncRNAs over time in ALS. We performed small RNA sequencing in a discovery cohort of 116 longitudinal serum samples from ALS 40 patients collected at 3- to 4-month intervals and identified tRNA-derived stress-induced RNA (tiRNA) tDR-1:34-Gly-GCC as the top sncRNA to increase over time. The finding was validated using TaqMan PCR and replicated in an independent cohort of 35 patients. Both univariate and joint model analyses showed that higher tDR-1:34-Gly-GCC levels correlated with shorter survival. Given that the translation of mRNAs and stress-induced translation inhibition are dysregulated in ALS and linked to familial ALS genes, combined with these findings, serum tDR-1:34-Gly-GCC tiRNA levels hold potential as a prognostic biomarker and outcome measure in clinical trials.