– SMNuHoMICS

Spinal Muscular Atrophy (SMA) is an autosomal recessive neuromuscular disease, which affects motoneurons. Children affected with SMA present difficulties in crawling, walking, breathing and swallowing. SMA is caused by bi-allelic mutations in the SMN1 gene, which encodes the protein Survival of Motor Neuron (SMN).
SMN is a multifunctional ubiquitous protein involved in many cellular processes, such as biogenesis and trafficking of ribonucleoproteins, local translation of messenger RNAs, etc. Several SMN functions rely on its association with arginine methylated proteins. Within the nucleus, SMN localizes in Cajal bodies (CB) and it has been shown that CB may associate with nucleoli. The nucleolus is a nuclear organelle dedicated to the transcription of ribosomal DNA (rDNA) by the RNA polymerase I (RNAP1) and early ribosomal RNA (rRNA) maturation; the first critical steps in ribosome biogenesis. The nucleolus is a highly organized structure that can be dynamically altered by both genotoxic agents and general cellular stress. Namely, after a genotoxic stress RNAP1, Fibrillarin (FBL) and nucleolar DNA are exported to the periphery of the nucleolus. Once DNA repair is fully completed the proper organization of the nucleolus is restored. Importantly, partners of this consortium have recently found that SMN shuttles from CB to the nucleolus after DNA repair completion but before the restoration of the nucleolar structure. Unexpectedly, they discovered that SMN is required for the restoration of nucleolar structure after DNA repair.
In this proposal, we built an international consortium of scientists interested in the field of nuclear and nucleolar dynamics and SMA disease which masters different omics approaches and have fully complementary expertises. Each partner of this consortium shares the same scientific interest in understanding the pathophysiology of SMA disease and the cellular functions of SMN.

Within this consortium, we propose:
To understand the function(s) of SMN in the nucleolus and the impact on the pathophysiology of SMA disease.

To reach this scientific objective, we have coordinated this consortium around 3 aims:

AIM 1: Validate newly discovered SMN nucleolar function in a motoneuron cellular model.

AIM 2: Identify the posttranscriptional modifications of rRNAs and U snRNAs in SMA models upon DNA repair-induced nucleolar reorganization.

AIM 3: Define the methylation profile of the nucleolar SMN interactome upon DNA repair-induced nucleolar reorganization.

Results from this research may directly impact the life and well-being of SMA patients, a specific approach based on our results, may lead to the development of prognosis and diagnosis approaches as well as supporting drugs that will retard the progression of the disease and delay the neurodegeneration of motoneurons in SMA patients.