Abstract
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease that results in progressive and worsening paralysis. Mutations in the TAR DNA-binding protein (TDP-43) have been implicated in both familial and sporadic cases of ALS, and aggregates of TDP-43 have been found in ALS patient derived brain tissue suggesting a central role of the protein in disease pathology. This protein is involved in a variety of RNA-related cellular processes including transcription, translation, splicing, and mRNA transport, and its levels are very tightly controlled within the cell. It has previously been shown that disrupting TDP-43 levels in Drosophila results in decreased survival, reduced growth of the neuromuscular junction (NMJ), and defective growth factor signaling. The BMP pathway is one growth factor signaling pathway that we have shown to be misregulated. One of the downstream targets of this pathway, phosphorylated-Mad (p-Mad), was decreased specifically at the synapse when TDP-43 was misexpressed, although its nuclear levels remained unaffected. Here I investigated two possible mechanisms through which TDP-43 dysfunction could act to bring about this selective loss in BMP signaling. First, excessive retrograde transport of p-Mad away from the synapse could be contributing to synapse-specific depletion. Second, recent work has suggested that in addition to canonical BMP signaling, glutamate receptors on the muscle help to regulate the synaptic p-Mad pool, and therefore reduction of post-synaptic glutamate receptors could lead to a decrease in pre-synaptic p-Mad. My results indicate that retrograde traffic is not contributing to the synaptic growth defects in our ALS model, but that GluRIIA levels appear to be reduced suggesting that this non-canonical pathway could be playing a role in disease pathology. Overall, my findings provide some important insight into what factors TDP-43 misregulation could be impinging upon in ALS, thus opening up new avenues for further exploration.