The ribonucleoprotein RBM20 regulates Tau splicing

The RNA binding motif type 20 (RBM20) protein is a trans-acting factor that regulates alternative splicing, highly expressed in striated muscle and heart. In the last years, our laboratory and others have shown that RBM20 affects the splicing of several mRNAs relevant to cardiac function. We demonstrated that the expression of RBM20 and polypyrimidine tract binding protein PTBP1 promoted the alternative shift of selected exons of FHOD3, a sarcomeric protein highly expressed in the cardiac tissue and required for the assembly of the contractile apparatus. The mis-splicing of some RBM20 targets as a consequence of mutations in the RBM20 gene results in progressive dilated cardiomyopathy (DCM), including atrial and ventricular arrhythmias. We recently contributed to a study that identifies dysregulated sarcoplasmic ribonucleoprotein granules in RBM20 geneedited animal models developing DCM. In the present study, we investigate the participation of RBM20 in regulating the exon splicing of MAPT gene transcripts encoding Tau protein, which plays a pivotal role in tubulin assembly and cytoskeleton stabilization. Tau isoforms are intensively regulated by alternative splicing and their mis-splicing is associated with neurodegenerative diseases such as Alzheimer’s Disease. By in silico analyses, we identified putative cis-acting sequences in the flanking intron regions required for Tau exon 6 splicing. We produced a minigene containing the exon 6 region and analyzed the pattern of expression of exon 6 transcript variants in a cell model overexpressing by transfection RBM20 or PTBP1. The preliminary results indicate that RBM20 and PTBP1 contribute to Tau exon 6 skipping and support the hypothesis that Tau may be a novel RBM20 target for tissue-specific alternative splicing regulation and may have a role in ribonucleoprotein complexes deregulation associated with tauopathies.