Deciphering the circular RNAs landscape in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons, with most cases lacking a clear genetic basis. Emerging evidence highlights the involvement of non-coding RNAs, particularly circular RNAs (circRNAs), in disease onset and progression. In this study, we investigated circRNAs implicated in ALS and related motor neuron diseases (MNDs). First, we conducted a systematic review to identify ALS-associated circRNAs, followed by in silico analyses of 15 selected candidates. Our results revealed that hsa_circ_0000099, hsa_circ_0001017, hsa_circ_004846, and hsa_circ_0034880 regulate a high number of ALS-related genes through miRNA sponging. Pathway enrichment analysis indicated that hsa_circ_0000099 is particularly involved in unfolded protein response, oxidative stress, cell cycle regulation, and apoptosis. Protein–RNA interaction analysis further showed that ALS-related circRNAs can sponge 20 RNA-binding proteins, with FMR1, ELAVL1, EIF4A3, and SRSF1 exhibiting the highest number of interactions. Additionally, molecular docking analysis demonstrated that FUS mutations significantly alter its binding affinity to hsa_circ_0000567 and hsa_circ_0060762. RNA-seq data from ALS patients confirmed significant alterations in the expression of host genes of ALS-related circRNAs and hub proteins across affected tissues, including the spinal cord and multiple brain regions. Collectively, these findings support circRNAs as active contributors to ALS pathogenesis. In particular, the host gene of hsa_circ_0000099, which is expressed in the spinal cord and hippocampus, emerges as a potential biomarker for tissue-specific impairment in ALS. Moreover, its regulatory role in key ALS-related cellular pathways underscores its promise as a candidate for biomarker development and therapeutic targeting. Further experimental validation is warranted to confirm its role in ALS pathology.