Oncogenes and transcription factors long non coding RNA: new actors in ALS pathogenesis

Background. Alteration in RNA metabolism, concerning both coding and long non coding RNAs (lncRNAs), may play an important role in ALS pathogenesis. Moreover, deep transcriptome studies showed numerous data that highlighted deregulation not only in gene known to be ALS linked, but also in gene associated with non-canonical pathways, such as cancer. Some evidences support the idea that cancer and neurodegenerative disorders share some common pathways. Results. About this point, RNA-seq data in peripheral blood mononuclear cells (PBMCs) from ALS patients and controls showed an important deregulation in the oncogene c-MYC and also in some transcriptor factors, such as ZEB1, associated to colon cancer. Interesting, for both c-MYC and ZEB1 gene we have also found deregulated the respective lncRNAs antisense, MINCR and ZEB1-AS. About c-MYC, we have found a down-regulation in ALS of mRNAs MINCR and MYC binding protein, while c-MYC mRNAs has been found up-regulated. Western blotting analysis showed that MYCBP protein levels were reduced in ALS patients, whereas protein levels of c-MYC did not show differences. We have investigated MAX, a protein that interacts with c-MYC for the heterodimer formation; Max immunoprecipitation revealed that c-MYC binds Max more in control subjects than in ALS patients. About ZEB1, ZEB1-AS and its coding gene has been found down-regulated in ALS patients. ZEB1 may act as repressor or activator of transcription, it may repress histones organization or activate chromatin regulators. Moreover, ZEB1-AS has already been characterized in cancer, in fact has been demonstrated that higher expression values of ZEB1-AS promote tumor metastasis. Conclusions. Our data showed an important involvement of tumor actors characterized by a regulation opposite respect what have been described in cancer. This investigation may offer numerous starting points for new investigations about pathogenic mechanism involved in ALS disease.