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Spinal muscular atrophy is a devastating disease that is characterized by degeneration and death of a specific subclass of motor neurons in the anterior horn of the spinal cord. Although the gene responsible, survival motor neuron 1 ( SMN1 ), was identified 20 years ago, it has proven difficult to investigate its effects  in vivo.  Consequently, a number of key questions regarding the molecular and cellular functions of this molecule have remained unanswered. We developed a  Caenorhabditis elegans  model of  smn-1  loss-of-function using a neuron-specific RNA interference strategy to knock-down  smn-1  selectively in a subclass of motor neurons. The transgenic animals presented a cell-autonomous, age-dependent degeneration of motor neurons detected as locomotory defects and the disappearance of presynaptic and cytoplasmic fluorescent markers in targeted neurons. This degeneration led to neuronal death as revealed by positive reactivity to genetic and chemical cell-death markers. We show that genes of the classical apoptosis pathway are involved in the  smn-1 -mediated neuronal death, and that this phenotype can be rescued by the expression of human  SMN1 , indicating a functional conservation between the two orthologs. Finally, we determined that  Plastin3/plst-1  genetically interacts with  smn-1  to prevent degeneration, and that treatment with valproic acid is able to rescue the degenerative phenotype. These results provide novel insights into the cellular and molecular mechanisms that lead to the loss of motor neurons when  SMN1  function is reduced.

Neuron-specific knock-down of SMN1 causes neuron degeneration and death through an apoptotic mechanism