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SPINAL MUSCULAR ATROPHY RESEARCH PROJECTS

Modeling Spinal Muscular Atrophy in Drosophila

Anindya Sen, Guruharsha Kuthethur and Douglas Dimlich

Collaborators: Laboratories of Anne Hart (Brown University), Lee Rubin (Harvard Stem Cell Institute) and David Van Vactor (HMS, Dept. of Cell Biology), Dan Curtis (Novartis Institute for Biomedical Research, Boston)

Spinal Muscular Atrophy (SMA), a recessive hereditary neurodegenerative disease in humans, has been linked to mutations in the Survival of Motor Neuron (SMN) gene. SMA patients display early onset lethality coupled with motor neuron loss and skeletal muscle atrophy. We currently employ Drosophila, which encodes a single SMN ortholog, Survival of motor neuron (Smn), to model SMA, since reduction of Smn function leads to defects that mimic SMA pathology in humans. We have demonstrated that a normal neuromuscular junction (NMJ) structure depends on Smn expression and that Smn protein concentrates in the post-synaptic NMJ regions. In addition, we have taken a genetic approach to identify modifiers of Smn to further define the cellular process affected by Smn loss. These screens have resulted in the recovery of a large number of modifiers, thereby expanding the genetic circuitry of Smn to include several genes not previously associated with this locus. Among the identified modifiers were representatives of several signaling pathways, most notably the BMP and FGF pathways. As both of these pathways have been demonstrated to affect the structure and function of mammalian nervous systems, our results confirm that a genetic approach is likely to identify bona fide modulators of Smn activity and, as a consequence, may identify putative therapeutic targets whose modulation may help to alleviate symptoms of the disease in SMA patients