The role of axonal mRNA translation in Amyotrophic Lateral Sclerosis (resubmission)

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Amyotrophic lateral sclerosis (ALS) is a devastating disease caused by the degeneration of motor neurons leading to paralysis and death usually 2-5 years after onset of symptoms. Currently no cure or disease-modifying therapies exist, partly because we still lack basic understanding of the root-cause of the disease. To devise better therapeutic strategies, we need a greater understanding of the molecular and cellular mechanisms responsible for this selective neuronal degeneration. The vast majority of cases are sporadic while 5-10% are inherited. Studying the gene alterations that cause the disease in a rare few cases gives important clues into the causes. Functional studies of mutations that cause the disease have begun to implicate a number of mechanisms. One key mechanism that is emerging is the dysregulation of RNA biology. Current evidence indicates that multiple aspects of mRNA formation and handling are affected in disease conditions, including expression, maturation, stability, subcellular distribution and translation. The key question now is why disruption of mRNA handling leads specifically to the demise of motor nerves to cause ALS. A unique characteristic of motor nerves is their extraordinary length; many times longer than most other nerve types. In recent years, it has become clear that mRNAs can travel to the nerve extremities where they provide templates for local translation to support essential synaptic functions. Bringing these ideas together, we hypothesise that disruptions to the myriad of normal RNA regulatory processes leads to alterations in the population of mRNAs available for translation in motor nerve termini is an important trigger in how ALS starts. To explore this idea, we will determine which mRNA molecules are underdoing translation in adult motor nerve axons in vivo. We will then seek to understand how this profile changes during ageing and under disease conditions. Importantly, this work will go beyond the in vitro conditions of cultured cells by conducting our analysis in an animal model, Drosophila melanogaster. We will address these fundamental questions using the disease-relevant cell type (motor neurons) in their native environment, in an intact neuromuscular circuit. For time, cost and ethical considerations, invertebrate models provide many advantages yet have proven functional similarities to mammalian motor nerves. Moreover, using a genetically tractable animal model will allow us to define the pathological relevance of the mRNAs that are dysregulated by determining their functional impact on the disease-relevant circuits at an organismal level. This type of discovery research is essential to lay the foundations for a clearer understanding of the disease cause to develop more effective therapies.