Through an intimate set of collaborative interactions with three other laboratories working in invertebrate and mammalian systems, we have developed a genome-wide approach to define the conserved functional "interactome" for Survival of Motor Neurons (SMN), the highly conserved gene family causal to over 95% of Spinal Muscular Atrophy (SMA), one of the most common degenerative motor neuron diseases in humans. Through recent studies, Drosophila has emerged as a promising genetic model for Smn with the key hallmarks of human SMA, from failure of neuromuscular junctions to the degeneration of neurons and muscles. Despite an emphasis in the SMA field to focus on mouse models, the innovative use of invertebrate species to understand SMN biology and define conserved and potentially druggable effector pathways was recently supported by a patient advocacy group (the SMA Foundation). Our analysis of Smn modifier mutations and compounds/factors derived from chemical and genetic screens in Drosophila, C. elegans and human cells has identified several strong and conserved candidate pathways, including the Bone-Morphogenic Protein (BMP)-family signaling pathway known to control neuromuscular junction (NMJ) development in flies. Modulation of this BMP retrograde synaptic signaling pathway alone can potently attenuate key NMJ phenotypes of Smn loss in Drosophila. Therefore, in addition to completion of our secondary screens to define the Smn functional network, we here propose parallel levels of analysis to determine precisely how loss of Smn disrupts BMP signaling, and to what extent manipulation of the highly conserved elements in the BMP pathway can reverse the defects in neuromuscular structure and function resulting from reduced Smn activity. We will apply a combination of genetic, biochemical and developmental analyses to answer these questions, as we continue to identify the other conserved effectors downstream of SMN.
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