The role of SMN protein in translation: implications for Spinal Muscular Atrophy

Spinal Muscular Atrophy (SMA) is the most common genetic cause of infant mortality, with an incidence of 1 in 6-10.000 live births. SMA is a devastating disease caused by genetic defects in the Smn gene, which induces loss of SMN protein and loss of neurons involved in muscle contraction. These defects lead to muscle atrophy and eventually to paralysis. Despite very encouraging developments, it is clear that SMN-targeted therapies are not sufficient to “cure” SMA patients. Further studies are required to understand the functional role of SMN and develop more effective therapeutic options. Our project aims to fill this gap, by going back to the basis and studying the connection between SMN protein and ribosomes, the cellular machineries producing all proteins in cells. This proposal will use fundamental scientific research to generate important insights into the cellular mechanisms leading to disease. Taking advantage of mouse models of the disease and cutting edge sequencing technologies, we aim to understand the molecular basis of the interaction between SMN protein and ribosomes, revealing the mechanism behind the profound defects in protein production in SMA. The discovery of key molecular functions of SMN during the critical period of neuromuscular development has important potential implications for better understanding the effects of current therapies and foster the design of next generation of therapies for SMA patients. Finally, the combination of cutting-edge next generation sequencing may not only shed light on the mechanisms underlying SMA disease but also identify potential molecular markers for disease progression and new therapeutic targets related to the ribosome, which can be exploited in the future for SMA and, potentially, related conditions.