Ricerc@Sapienza

Regulatory non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), and RNA binding proteins (RBPs) represent important modulators of cell fate identity. In particular, ncRNAs and RBPs are remarkably abundant in the nervous system where they exert important regulatory functions.
The present proposal stems from a 2014 ERC Starting Grant project (acronym: NeuRNA) aimed at studying ncRNAs involved in human early neural development. Here we propose to extend this aim by systematically identifying ncRNAs that play a role during neural development AND neurodegeneration, using the motoneuron disease Amyotrophic Lateral Sclerosis (ALS) as a paradigm. In the last few years, indeed, it has been proposed that dysregulation of RNA metabolism could be a trigger to motoneuron degeneration. We will therefore explore the possibility that neural ncRNAs, which we name NeuRNAs (for Neural untranslated RNA), might be under the control of RBPs mutated in ALS, such as FUS. Our lab has recently established a collection of human induced Pluripotent Stem Cells (iPSCs) with ALS mutations in the FUS gene. We have also set up proper protocols for differentiating iPSCs into different subtypes of motor and cortical neurons. Together with our expertise in the non-coding RNA field, these tools put us in the ideal position to accomplish the proposed aims.
In the first aim we will profile NeuRNAs from differentiating iPSCs, identifying specific neural signatures, and provide a functional and mechanistic characterization of relevant candidates. In the second aim we will assess whether NeuRNAs are under the control of ALS-linked RBPs and whether ALS mutations affect their activity. Our work will investigate about the contribution of the non protein-coding portion of our genome to fundamental processes such as neural development and neurodegeneration.