LncRNAs involved in neuronal development seem to play a role in ALS pathology

Neuronal proliferation and development process play a role in ALS, with studies demonstrating how in G93A-SOD1 mice ependymal stem progenitor cells show a higher proliferation and differentiation towards the neuronal lineage. Moreover, human derived neural progenitor cells from ALS patients tend to differentiate to neuronal lineages. LncRNAs play a role in neuronal cell’s development, and the ablation of a panel of 8 lncRNAs causes strong modifications in mouse brain’s development. Recently, we investigated the role of these 8 lncRNAs in neuronal stem cell differentiation. We identified an interaction between HuR (ELAVL1) and these lncRNAs. We found AU-rich regions within their sequences and by RNA-Immunoprecipitation we demonstrated that the lncRNAs bind HuR. Furthermore, both pharmacological and genetic inhibition of HuR lead to a modification in their metabolism. We then decided to investigate the role of six of these lncRNAs (lincENC1, lincBRN1a, lincBRN1b, TUG1, FENDRR, lincp21) in ALS pathology. Their expression was investigated in different spinal cord (SC) areas (cervical, thoracic and lumbar) of G93A-SOD1 mice, both at a pre-symptomatic stage (8 weeks of age) and at a symptomatic stage (18 weeks of age). In the 8W mice, lincBRN1a was up-regulated in the SOD1-G93A lumbar SC. For 18W mice, lincp21 was up-regulated both in the cervical and in the thoracic SC and an increase in lincENC1 was observed in the SOD1-G93A thoracic SC. Furthermore, we found an up-regulation in lincBRN1b expression from the 8W to the 18W stage in the cervical SC, indicating a potential role for this lncRNA in the neuronal aging process. Together, these data highlight a potential role for lncRNAs in disease onset and progression. The understanding of how these lncRNAs influence the ALS pathology may elucidate new targetable pathways.