LncRNAs associated with neuronal development and oncogenesis are deregulated in SOD1-G93A murine model of Amyotrophic Lateral Sclerosis

Introduction: Studies in familial Amyothrophical Lateral Sclerosis (fALS), are implicating more and more neuronal proliferation and differentiation. It has been shown that in the familial preclinical SOD1-G93A ALS murine model, ependymal stem progenitor cells show a higher proliferation and differentiation towards the neuronal lineage. 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. Materials and Methods: lncRNAs were investigated in three different spinal cord areas (cervical, thoracic, and lumbar) and in four brain areas (prefrontal cortex, motor cortex, hippocampus, striatum) of pre-symptomatic (8 Weeks) and symptomatic (18 weeks) in SOD1-G93A mice. Six human homologues (lincBRN1a, TUG1, lincp21, FENDRR, HOTTIP and ELDR) were identified and their expression was investigated in SH-SY5Y cells expressing the hSOD1-G93A gene. Results: The lncRNAs expression profile was deregulated in all analyzed areas. Linc-p21 presented an alteration in its expression levels in all analyzed areas at 18 Weeks. We also found a p53 upregulation in symptomatic SOD1-G93A mice, indicating a deregulation in the p53/linc-p21/p21 pathway. Tug1, which was found upregulated in the lumbar spinal cord at both 8 and 18 weeks of age. In relation to this we found an increased expression of its down-stream targets Tril/Tlr4, indicating an on-going inflammatory phenomenon. For linc-Brn1a and linc-Brn1b we found a predominant deregulation in the pre-symptomatic mice, suggesting they could be relevant in early phases of CNS development of G93A disease model. A reduced, although present, deregulation was found for Hottip, Eldrr, Linc-Enc1, and Fendrr. In SH-SY5Y-SOD1G93A, the 6 human homologues resulted deregulated versus the wild-type cell line. Conclusions: This study is the first characterization of a panel of 8 lncRNAs in ALS, indicating a deregulation in all their expression in specific ALS affected areas at different stages of the pathogenesis. The analysis in SH-SY5Y-SOD1G93A indicates a possible translation of these results the human fALS pathology.