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

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.