Implication of the oncogenic lncRNA ZEB1-AS1 mediated pathway in sporadic ALS pathogenesis

Background. The implication of RNA expression in the pathogenesis of sporadic ALS (sALS) is becoming increasingly relevant, with RNA-seq data highlighting numerous deregulated long non-coding RNAs (lncRNAs) in tissues derived from sALS patients. Among these, the oncogenic lncRNA ZEB1-AS1 emerged as strongly downregulated in peripheral blood mononuclear cells (PBMCs) of sALS patients. In cancer-derived cell lines, ZEB1-AS1 has been shown to act in a feedback negative loop with mir200c, acting as a molecular sponge for this miRNA. Furthermore, ZEB1-AS1’s interaction with mir200c results in the upregulation of the downstream molecule BMI1. Interestingly, it has been shown that FUS plays a role in the biogenesis of mir200c. Results. In PBMCs and spinal cords of sALS patients versus healthy controls we observed a downregulation of ZEB1-AS1’s expression but not of its sense gene ZEB1. We created an in vitro model silencing ZEB1-AS1 in SH-SY5Y. This downregulation does not influence ZEB1’s levels, mimicking what observed in sALS. On the contrary, we observed an increase of mir200c and a decrease of BMI1, in an opposite pattern to what is observed in cancer, suggesting a possible sALS involved pathway. Concordantly, we found that BMI1 is also downregulated in PBMCs of sALS patients. We demonstrated that ZEB1-AS1 can bind the ALS-implicated RNA binding protein FUS, and we demonstrated this both in SH-SY5Y cells and in PBMCs. Interestingly, we saw that there is a reduction in the amount of ZEB1-AS1 bound to FUS in sALS patients. Conclusions. Our results show an implication of the ZEB1-AS1 pathway in sALS. The downregulation of ZEB1-AS1 leads to an increase of mir200c and a subsequent downregulation of BMI1, in an opposite trend to what is observed in cancer-derived cell lines. Furthermore, we report an interaction of ZEB1-AS1 with FUS, impaired in sALS patients, suggesting the mechanism connecting ZEB1-AS1 to sALS pathology.