Global deregulation of lncRNAs involved in neuronal development could play a role in ALS

INTRODUCTION: Studies in Amyotrophic Lateral Sclerosis (ALS), are implicating more and more neuronal proliferation and differentiation. Indeed, it has been shown that in the familial preclinical SOD1-G93 ALS murine model, 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 (lincENC1, lincBRN1a, lincBRN1b, TUG1, FENDRR, lincp21, HOTTIP and ELDR) causes strong modifications in mouse brain’s development. We decided to study the potential involvement of these lncRNAs in ALS pathology. METHODS: The lncRNAs were investigated in three different spinal cord (SC) areas (cervical, thoracic and lumbar) and in four brain areas (prefrontal cortex, motor cortex, hippocampus, striatum) of symptomatic 18 weeks of age SOD1-G93A mice. Furthermore, 6 human homologues (lincBRN1a, TUG1, lincp21, FENDRR, HOTTIP and ELDR) were identified and their expression was investigated in an in vitro model of the disease (SH-SY5Y cells transfected with the SOD1-G93A gene). RESULTS: The lncRNAs expression profile was deregulated in all analyzed areas. Interestingly, there is a specific alteration pattern in the brain compared to the SC. Indeed, lincBRN1a, lincBRN1b and TUG1 resulted specifically deregulated in the more central areas, whereas HOTTIP, ELDR and ENC presented a spinal cord-specific deregulation. It emerged how lincp21 (already partially characterized as a lncRNAs involved in the p53 oncogene regulation pathway) was deregulated in all the affected areas. Indeed, p53, key activator of lincp21, resulted upregulated in the analyzed spinal cord areas, concordantly with lincp21’s expression. In SH-SY5Y-SOD1G93A, the 6 human homologues all resulted deregulated versus the wild-type cell line. DISCUSSION & CONCLUSIONS: These results allowed to identify the CNS areas specific lncRNAs deregulation, classifying the lncRNAs between those more implicated in brain versus those more implicated in the SC of ALS models. The analysis in an in vitro human cellule model of the disease indicates a possible translation of these results the human ALS pathology. This global screening lead to identify one potentially crucial regulator: lincp21.