The Interplay between Local Synthesis and Axon/NMJ Maintenance and Degeneration

In order to survive and maintain their function, cells depend on spatiotemporal signaling and metabolic processes, that can be regulated via local proteins synthesis events. Alterations is such process can cause cell death and diseases. In neurons, which are highly polarized cells, localization of mRNAs and miRNAs together with local synthesis events at distinct subcellular compartments, is critical for the neurons’ ability to respond to inter and intra cellular changes. Amyotrophic lateral sclerosis (ALS) is a lethal motor neuron disease, with no available treatment. Although the basic mechanism of the disease remains poorly understood, spatial alteration in RNA metabolism and local synthesis is thought to be a key player in disease toxicity. Indeed, mutations in RNA binding proteins (RBPs), that are essential for proper localization of RNAs at distinct places along the axon, were identified in ALS patients. Still, the identity of the RNA nature of these RBPs, and the specific functional role they play, remain poorly understood. Here we suggest to study the role of RBPs in shuttling mRNAs long distances in neurons, departing from the cell body and localizing them at distinct foci of local synthesis along the axon and synapse. Specifically, we aim to understand whether transcripts coding for proteins with complementary functions are co-packaged with the RNA binding proteins: TDP-43, Elavl2 and staufen1, that alter in ALS, and whether there is a specific association of RBPs with discrete sets of mRNAs coding for functionally related proteins.